7-acylamino-3-vinylcephalosporanic acid derivatives useful for treatment of infectious diseases in human beings and animals

ABSTRACT

The invention relates to novel compounds of high antimicrobial activity of the formula: ##STR1## in which R 1  is amino-substituted-heterocyclic group which may have halogen, protected amino-substituted-heterocyclic group which may have halogen, or a group of the formula: ##STR2## wherein R 3  is lower alkyl, 
     R 2  is carboxy or a protected carboxy group, and 
     A is lower alkylene which may have a substituent selected from the group consisting of amino, a protected amino group, hydroxy, oxo and a group of the formula: ═N˜OR 4 , wherein R 4  is hydrogen, cyclo(lower)alkenyl, lower alkynyl, lower alkenyl, lower alkenyl substituted by carboxy or a protected carboxy group, lower alkyl, or lower alkyl substituted by one or more substituents selected from carboxy, a protected carboxy group, amino, a protected amino group, cyano, phosphono, a protected phosphono group and a heterocyclic group which may have suitable substituents.

This is a division of application Ser. No. 205,334, filed Nov. 10, 1980,now U.S. Pat. No. 4,409,214.

The present invention relates to novel7-acylamino-3-vinylcephalosporanic acid derivatives and pharmaceuticallyacceptable salts thereof.

More particularly, it relates to novel7-acylamino-3-vinylcephalosporanic acid derivatives and pharmaceuticallyacceptable salts thereof, which have antimicrobial activity, toprocesses for the preparation thereof, to a pharmaceutical compositioncomprising the same, and to a method of using the same therapeuticallyin the treatment of infectious diseases in human being and animals.

Accordingly, one object of the present invention is to provide novel7-acylamino-3-vinylcephalosporanic acid derivatives and pharmaceuticallyacceptable salts thereof, which are highly active against a number ofpathogenic microorganisms and are useful as antimicrobial agents,especially for oral administration.

Another object of the present invention is to provide processes for thepreparation of novel 7-acylamino-3-vinylcephalosporanic acid derivativesand salts thereof.

A further object of the present invention is to provide a pharmaceuticalcomposition comprising, as active ingredients, said7-acylamino-3-vinylcephalosporanic acid derivatives and pharmaceuticallyacceptable salts thereof.

Still further object of the present invention is to provide a method ofusing said 7-acylamino-3-vinylcephalosporanic acid derivatives andpharmaceutically acceptable salts thereof in the treatment of infectiousdiseases by pathogenic microorganisms in human being and animals.

The object 7-acylamino-3-vinylcephalosporanic acid derivatives are noveland can be represented by the following general formula: ##STR3## inwhich R¹ is amino-substituted-heterocyclic group which may have halogen,protected amino-substituted-heterocyclic group which may have halogen,or a group of the formula: ##STR4## wherein R³ is lower alkyl, R² iscarboxy or a protected carboxy group, and

A is lower alkylene which may have a substituted selected from thegroups consisting of amino, a protected amino group, hydroxy, oxo and agroup of the formula: ═N˜OR⁴, wherein R⁴ is hydrogen,cyclo(lower)alkenyl, lower alkynyl, lower alkenyl, lower alkenylsubstituted by carboxy or a protected carboxy group, lower alkyl, orlower alkyl substituted by one or more substituent(s) selected fromcarboxy, a protected carboxy group, amino, a protected amino group,cyano, phosphono, a protected phosphono group and a heterocyclic groupwhich may have suitable substituent(s).

In the object compounds (I) and the corresponding starting compounds(II) to (VI) in Processes 1, 5 and 7 mentioned below, it is to beunderstood that there may be one or more stereoisomeric pair(s) such asoptical and geometrical isomers due to asymmetric carbon atom and doublebond in those molecules and such isomers are also included within thescope of the present invention.

With regard to geometrical isomers in the object compounds and thestarting compounds, it is to be noted that, for example, the objectcompounds, wherein A means a group of the formula: ═C═N˜OR⁴, include synisomer, anti isomer and a mixture thereof, and the syn isomer means onegeometrical isomer having the partial structure represented by thefollowing formula: ##STR5## wherein R¹ and R⁴ are each as defined above,and the anti isomer means the other geometrical isomer having thepartial structure represented by the following formula: ##STR6## whereinR¹ and R⁴ are each as defined above.

Regarding the other object and starting compounds as mentioned above,the syn isomer and the anti isomer can also be referred to the samegeometrical isomers as illustrated for the compounds (I).

Suitable pharmaceutically acceptable salts of the object compounds (I)are conventional non-toxic salts and may include a salt with a base oran acid addition salt such as a salt with an inorganic base, forexample, an alkali metal salt (e.g. sodium salt, potassium salt, etc.),an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.),an ammonium salt; a salt with an organic base, for example, an organicamine salt (e.g. triethylamine salt, pyridine salt, picoline salt,ethanolamine salt, triethanolamine salt, dicyclohexylamine salt,N,N'-dibenzylethylenediamine salt, etc.) etc.; an inorganic acidaddition salt (e.g. hydrochloride, hydrobromide, sulfate, phosphate,etc.); an organic carboxylic or sulfonic acid addition salt (e.g.formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate,benzenesulfonate, p-toluenesulfonate, etc.); a salt with a basic oracidic amino acid (e.g. arginine, aspartic acid, glutamic acid, etc.);an intermolecular or intramolecular quaternary salt, and the like. Thesaid intermolecular quaternary salt can be formed in case that theheterocyclic group in R⁴ in the compounds (I) contains nitrogen atom(s)(e.g. pyridyl, etc.), and suitable intermolecular quaternary salt mayinclude. 1-lower alkylpyridinium lower alkylsulfate (e.g.1-methylpyridinium methylsulfate, 1-ethylpyridinium ethylsulfate, etc.),1-lower alkylpyridinium halide (e.g. 1-methylpyridinium iodide, etc.)and the like. The said intramolecular salt can be formed in case thatheterocyclic group in R⁴ in the compounds (I) contains nitrogen atom(s)(e.g. pyridyl etc.) and R² is carboxy, and suitable intramolecular saltmay include 1-lower alkylpyridinium carboxylate (e.g. 1-methylpyridiniumcarboxylate, 1-ethylpyridinium carboxylate, 1-propylpyridiniumcarboxylate, 1-isopropylpyridinium carboxylate, 1-butylpyridiniumcarboxylate, etc.); and the like.

According to the present invention, the object compounds (I) and thepharmaceutically acceptable salts thereof can be prepared by theprocesses as illustrated by the following reaction schemes. ##STR7## inwhich R¹, R² and A are each as defined above,

R_(a) ¹ is protected amino-substituted-heterocyclic group which may havehalogen,

R_(b) ¹ is amino-substituted-heterocyclic group which may have halogen,

R_(a) ² is a protected carboxy group,

R_(b) ² is lower alkoxycarbonyl substituted by a protected amino and aprotected carboxy groups,

R_(c) ² is lower alkoxycarbonyl substituted by amino and carboxy,

R⁵ is lower alkyl,

R⁶ is amino or a protected amino group,

R⁷ is aryl,

A¹ is lower alkylene having a group of the formula: ═N˜OR_(a) ⁴, whereinR_(a) ⁴ is lower alkyl substituted by a protected carboxy group or aprotected phosphono group, or lower alkenyl substituted by a protectedcarboxy group,

A² is lower alkylene having a group of the formula: ═N˜OR_(b) ⁴, whereinR_(b) ⁴ is lower alkyl substituted by carboxy or phosphono, or loweralkenyl substituted by carboxy,

A³ is lower alkylene having a group of the formula: ═N˜OR_(c) ⁴, whereinR_(c) ⁴ is lower alkoxycarbonyl(lower)alkyl substituted by a protectedamino and a protected carboxy groups, or lower alkyl substituted by aprotected amino and a protected carboxy groups,

A⁴ is lower alkylene having a group of the formula: ═N˜OR_(d) ⁴, whereinR_(d) ⁴ is lower alkoxycarbonyl(lower)alkyl substituted by amino andcarboxy, or lower alkyl substituted by amino and carboxy,

A⁵ is lower alkylene having a group of the formula: ═N˜OR_(e) ⁴, whereinR_(e) ⁴ is lower alkyl substituted by a group of the formula: ##STR8##A⁶ is lower alkylene having a group of the formula: ═N˜OR_(f) ⁴, whereinR_(f) ⁴ is lower alkyl substituted by a group of the formula: ##STR9##wherein R⁵ is as defined above, A⁷ is lower alkylene having a group ofthe formula: ═N˜OR_(g) ⁴, wherein R_(g) ⁴ is lower alkyl substituted bya cation of the formula: ##STR10## wherein R⁵ is as defined above, A⁸ islower alkylene having a protected amino group,

A⁹ is lower alkylene having amino,

A¹⁰ is lower alkylene having oxo,

A¹¹ is lower alkylene having hydroxy,

A¹² is lower alkylene having a group of the formula: ═N˜OR⁴, wherein R⁴is as defined above, and

X¹ is halogen.

Some of the starting compounds (II), (III), (IV), (VI) and (VIII) usedin Processes 1, 5, 7 and 15 are new and can be represented by thefollowing general formulae: ##STR11## in which R_(A) is a group of theformula: ##STR12## wherein R⁸ is aryl,

R^(a) is a protected amino group,

R^(b) is a protected carboxy group, and

R¹ and A are each as defined above,

R_(B) is a group of the formula:

    --CH.sub.2 --X.sup.2, --CH.sub.2 P.sup.⊕ (R.sup.7).sub.3.X.sup.3.spsp.⊖ or --CH═P(R.sup.7).sub.3

wherein

X² and X³ are each halogen, and

R⁷ is as defined above, and

R² is as defined above; provided that, when R_(A) is a group of theformula:

R⁸ --CH═N--, wherein R⁸ is as defined above, then R_(B) is a group ofthe formula:

    --CH.sub.2 P.sup.⊕ (R.sup.7).sub.3.X.sup.3.spsp.⊖ or --CH═P(R.sup.7).sub.3, wherein

R⁷ and X³ are each as defined above, or a salt thereof; and ##STR13## inwhich R_(C) is amino or a group of the formula: ##STR14## wherein R^(c)and R^(d) are combined to form oxo or a protected oxo group, and

R⁸, R^(a), R^(b), A¹² and X¹ are each as defined above, and

R² is as defined above; provided that, when R_(C) is amino, then R² iscarboxy,

or a salt thereof; and ##STR15## in which R_(D) is amino or a protectedamino group, and R_(b) ² is as defined above, or a salt thereof; and

○4 R_(c) ¹ --A--R^(e) (Compound ○4 ) in which R_(c) ¹ is a group of theformula: ##STR16## wherein R^(f) is amino or trihalomethyl, and

R^(g) is carboxy or a protected amino group,

R^(e) is carboxy or a protected carboxy group, and

A is as defined above, or a salt thereof; and

○5 R¹ --A¹³ --R^(e) (Compound ○5 ) in which

A¹³ is lower alkylene having a group of the formula: ═N˜OR_(h) ⁴,wherein R_(h) ⁴ is lower alkenyl substituted by carboxy or a protectedcarboxy group, lower alkyl substituted by a protected amino and aprotected carboxy groups, lower alkyl substituted by a protected amino-and a protected carboxy-substituted-lower alkoxycarbonyl, or lower alkylsubstituted by pyridyl, and

R¹ and R^(e) are each as defined above, or a salt thereof; and

○6 R_(d) ¹ --A¹⁴ --R^(e) (Compound ○6 ) in which

R_(d) ¹ is aminothiazolyl having halogen, protected aminothiazolylhaving halogen, aminopyridyl, protected aminopyridyl, aminopyrimidinylor protected aminopyrimidinyl,

A¹⁴ is lower alkylene having a group of the formula: ═N˜OR_(i) ⁴,wherein R_(i) ⁴ is lower alkyl substituted by carboxy or a protectedcarboxy group, and

R^(e) is as defined above, or a salt thereof; and

○7 R^(h) --O--R_(h) ⁴ (Compound ○7 ) in which

R^(h) is amino or phthalimido, and

R_(h) ⁴ is as defined above, or a salt thereof.

Suitable salts of the starting compounds ○1 to ○7 thus formulated mayinclude the same ones as exemplified for the compounds (I).

The starting compounds ○1 to ○7 and other starting compounds can beprepared, for example, from the known compounds by the methods in thefollowing Processes ○1 to ○11 or in a similar manner thereto or in aconventional manner. ##STR17## in which R_(A), R_(B), R_(C), R¹, R_(a)¹, R_(b) ¹, R_(c) ¹, R_(d) ¹, R², R_(a) ², R_(b) ², R_(h) ⁴, R_(i) ⁴,R⁷, R⁸, R^(a), R^(b), R^(c), R^(d), R^(e), A, A², A⁸, A⁹, A¹⁰, A¹¹, A¹²,A¹³, A¹⁴, X¹, X² and X³ are each as defined above,

R_(C) ' is amino or a group of the formula: ##STR18## or R⁸ --CH═N--wherein R⁸, R^(c), R^(d), A¹² and X¹ are each as defined above,

R_(C) " is amino or a group of the formula: ##STR19## wherein R^(c),R^(d), A¹² and X¹ are each as defined above, R_(D) ' and R^(g') are eacha protected amino group,

R^(c') and R^(d') are combined to form oxo group,

R^(f') is trihalomethyl,

R^(i) is a protected carboxy group,

A¹⁵ is lower alkylene,

A¹⁶ is lower alkylene having a group of the formula: ═N˜OR_(j) ⁴,wherein R_(j) ⁴ is lower alkenyl substituted by carboxy or a protectedcarboxy group, and

X⁴ is halogen.

In the above and subsequent description of the present specification,suitable examples and illustration of the various definitions to beincluded within the scope thereof are explained in detail as follows.

The term "lower" in the present specification is intended to mean agroup having 1 to 7 carbon atoms, unless otherwise indicated.

Suitable "lower alkyl" group may include straight or branched one suchas methyl, ethyl, propyl, ispropyl, butyl, isobutyl, pentyl, isopentyl,neopentyl, hexyl and the like, in which the preferred one is C₁ -C₄alkyl.

Suitable "lower alkenyl" group may include straight or branched one suchas vinyl, 1-propenyl, allyl, 1-(or 2- or 3-)butenyl, 1-(or 2- or 3- or4-)pentenyl, 1-(or 2- or 3- or 4- or 5-)hexenyl, 2-methyl-2-propenyl,and the like, in which the preferred one is C₂ -C₅ alkenyl.

Suitable "lower alkynyl" group may include straight or branched one suchas propargyl, 2-(or 3-)butynyl, 2-(or 3- or 4-)pentynyl, 2-(or 3- or 4-or 5-)hexynyl, and the like, in which the preferred one is C₂ -C₅alkynyl.

Suitable "cyclo(lower)alkenyl" group may include C₃ -C₇ cycloalkenylsuch as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl, and the like, in which the preferred one is C₅ -C₆cycloalkenyl.

Suitable "protected amino" group may include an amino group substitutedby a conventional amino-protective group which is used in penicillin andcephalosporin compounds, for example, acyl as mentioned below,ar(lower)alkyl such as mono-(or di or tri)phenyl(lower)alkyl (e.g.benzyl, benzhydryl, trityl, etc.), lower alkoxycarbonyl(lower)alkylideneor its enamine tautomer (e.g. 1-methoxycarbonyl-1-propen-2-yl, etc.),di(lower)alkylaminomethylene (e.g. dimethylaminomethylene, etc.), etc.

Suitable "acyl" may include an aliphatic acyl, an aromatic acyl, aheterocyclic acyl and an aliphatic acyl substituted with aromatic orheterocyclic group(s).

The aliphatic acyl may include saturated or unsaturated, acyclic orcyclic ones, such as lower alkanoyl (e.g. formyl, acetyl, propionyl,butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.),lower alkanesulfonyl (e.g. mesyl, ethanesulfonyl, propanesulfonyl,etc.), lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, etc.), loweralkenoyl (e.g. acryloyl, methacryloyl, crotonoyl, etc.), '(C₃-C₇)-cycloalkanecarbonyl (e.g. cyclohexanecarbonyl, etc.), amidino, andthe like.

The aromatic acyl may include aroyl (e.g. benzoyl, toluoyl, xyloyl,etc.), arenesulfonyl (e.g. benzenesulfonyl, tosyl, etc.), and the like.

The heterocyclic acyl may include heterocyclecarbonyl (e.g. furoyl,thenoyl, nicotinoyl, isonicotinoyl, thiazolylcarbonyl,thiadiazolylcarbonyl, tetrazolylcarbonyl, etc.), and the like.

The aliphatic acyl substituted with aromatic group(s) may includear(lower)alkanoyl such as phenyl(lower)-alkanoyl (e.g. phenylacetyl,phenylpropionyl, phenylhexanoyl, etc.), ar(lower)alkoxycarbonyl such asphenyl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl,phenethyloxycarbonyl, etc.), phenoxy(lower)alkanoyl (e.g. phenoxyacetyl,phenoxypropionyl, etc.), and the like.

The aliphatic acyl substituted with heterocyclic group(s) may includethienylacetyl, imidazolylacetyl, furylacetyl, tetrazolylacetyl,thiazolylacetyl, thiadiazolylacetyl, thienylpropionyl,thiadiazolylpropionyl, and the like.

These acyl groups may be further substituted with one or more suitablesubstituents such as lower alkyl (e.g. methyl, ethyl, propyl, isopropyl,butyl, pentyl, hexyl, etc.), halogen (e.g. chlorine, bromine, iodine,fluorine), lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy,butoxy, pentyloxy, hexyloxy, etc.), lower alkylthio (e.g. methylthio,ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio,etc.), nitro and the like, and preferably acyl having suchsubstituent(s) may be mono (or di or tri)halo(lower)-alkanoyl (e.g.chloroacetyl, bromoacetyl, dichloroacetyl, trifluoroacetyl, etc.), mono(or di or tri)halo(lower)-alkoxycarbonyl (e.g. chloromethoxycarbonyl,dichloromethoxycarbonyl, 2,2,2-tri-chloroethoxycarbonyl, etc.), nitro(or halo or lower alkoxy)phenyl(lower)alkoxycarbonyl (e.g.nitrobenzyloxycarbonyl, chlorobenzyloxycarbonyl,methoxybenzyloxycarbonyl, etc.), and the like.

Suitable "protected carboxy" group may include an esterified carboxygroup which is conventionally used in penicillin or cephalosporincompounds at their 3rd or 4th position thereof.

Suitable "ester moiety" in "esterified carboxy group" may include loweralkyl ester (e.g. methyl ester, ethyl ester, propyl ester, isopropylester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester,tert-pentyl ester, hexyl ester, etc.), lower alkenyl ester (e.g. vinylester, allyl ester, etc.), lower alkynyl ester (e.g. ethynyl eser,propynyl ester, etc.), lower alkoxy(lower)alkyl ester (e.g.methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester,1-methoxyethyl ester, 1-ethoxyethyl ester, etc.), loweralkylthio(lower)alkyl ester (e.g. methylthiomethyl ester,ethylthiomethyl ester, ethylthioethyl ester isopropylthiomethyl ester,etc.), amino- and carboxy-subsituted-lower alkyl ester (e.g.2-amino-2-carboxyethyl ester, 3-amino-3-carboxypropyl ester, etc.),protected amino- and protected carboxy-substituted-lower alkyl estersuch as lower alkoxycarbonylamino- and mono(or di totri)phenyl(lower)alkoxycarbonyl-substituted-lower alkyl ester (e.g.2-tert-butoxycarbonylamino-2-benzhydryloxycarbonylethyl ester,3-tert-butoxycarbonylamino-3-benzhydryloxycarbonylpropyl ester, etc.),mono(or di or tri)halo(lower)alkyl ester (e.g. 2-iodoethyl ester,2,2,2-trichloroethyl ester, etc.), lower alkanoyloxy(lower)alkyl ester(e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethylester, isobutyryloxymethyl ester, valeryloxymethyl ester,pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethyl ester,2-propionyloxyethyl ester, 1-acetoxypropyl ester, etc.), loweralkanesulfonyl(lower)alkyl ester (e.g. mesylmethyl ester, 2-mesylethylester, etc.), ar(lower)alkyl ester which may have one or moresubstituent(s) such as mono(or di or tri)phenyl(lower)alkyl ester whichmay have one or more suitable substituent(s) (e.g. benzyl ester,4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, benzhydrylester, trityl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzylester, 4-hydroxy-3,5-di-t-butylbenzyl ester, etc.), aryl ester which mayhave one or more suitable substituents (e.g. phenyl ester, tolyl ester,t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, salicylester, etc.), heterocyclic ester (e.g. phthalidyl ester, etc.), and thelike.

Suitable "protected phosphono group" may includeO,O-di(lower)alkylphosphono such as O,O-dimethylphosphono,O,O-diethylphosphono, O,O-dipropylphosphono, and the like.

Suitable "lower alkylene" group may include straight or branched onesuch as methylene, ethylene, trimethylene, propylene, tetramethylene,hexamethylene, and the like, in which the preferred one is C₁ -C₂alkylene and the most preferred one is methylene.

Suitable "heterocyclic" group in the "heterocyclic group which may havesuitable substituent(s)" as the substituent of the lower alkyl for R⁴may include saturated or unsaturated, monocyclic or polycyclicheterocyclic group containing at least one hetero-atom such as anoxygen, sulfur, nitrogen atom, and the like. And, especially preferableheterocyclic group may be heterocyclic group such as

unsaturated 3 to 8-membered(more preferably 5 or6-membered)heteromonocyclic group containing 1 to 4 nitrogen atom(s),for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl andits N-oxide, dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,triazolyl (e.g. 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl,2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g. 1H-tetrazolyl,2H-tetrazolyl, etc.) etc.;

saturated 3 to 8-membered(more preferably 5 or6-membered)heteromonocyclic group containing 1 to 4 nitrogen atom(s),for example, pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl,etc.;

unsaturated condensed heterocyclic group containing 1 to 4 nitrogenatom(s), for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl,quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc.;

unsaturated 3 to 8-membered(more preferably 5 or6-membered)heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl(e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.),etc.;

saturated 3 to 8-membered(more preferably 5 or6-membered)heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1to 3 nitrogen atom(s), for example, morpholinyl, sydnonyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 2 oxygenatom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl,benzoxadiazolyl, etc.;

unsaturated 3 to 8-membered(more preferably 5 or6-membered)heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl,thiadiazolyl (e.g. 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.

saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3nitrogen atom(s), for example thiazolidinyl, etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 2 sulfur atom(s), for example,thienyl, dihydrodithiinyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 2 sulfuratom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl,benzothiadiazolyl, etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing an oxygen atom, for example, furyl,etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing an oxygen atom and 1 to 2 sulfuratom(s), for example, dihydrooxathiinyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 2 sulfuratom(s), for example, benzothienyl, benzodithiinyl, etc.;

unsaturated condensed heterocyclic group containing an oxygen atom and 1to 2 sulfur atom(s), for example, benzoxathiinyl, etc. and the like.

Thus defined heterocyclic group may optionally be substituted by one toten, same or different, suitable substituent(s) such as: lower alkyl(e.g. methyl, ethyl, etc.); lower alkoxy (e.g. methoxy, ethoxy, propoxy,etc.); lower alkylthio (e.g. methylthio, ethylthio, etc.); loweralkylamino (e.g. methylamino, etc.); cyclo(lower)alkyl (e.g.cyclopentyl, cyclohexyl, etc.); cyclo(lower)alkenyl (e.g. cyclohexenyl;cyclohexadienyl, etc.); hydroxy; halogen (e.g. chloro, bromo, etc.);amino; protected amino as aforementioned; cyano; nitro; carboxy;protected carboxy as aforementioned; sulfo; sulfamoyl; imino; oxo;amino(lower)alkyl (e.g. aminomethyl, aminoethyl, etc.); and the like.

Suitable "heterocyclic" group in "amino-substituted-heterocyclic groupwhich may have halogen" for R¹ and R_(b) ¹, and "protectedamino-substituted-heterocyclic group which may have halogen" for R¹ andR_(a) ¹ may include thiazolyl, thiadiazolyl (e.g. 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.),oxadiazolyl (e.g. 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), pyridyl, pyrimidinyl,tetrazolyl (e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.), and the like.

Suitable "trihalomethyl" group may include trichloromethyl, and thelike.

Suitable "lower alkoxycarbonyl(lower)alkyl" group may includeethoxycarbonylmethyl, propoxycarbonylmethyl, 1- or2-ethoxycarbonylethyl, and the like.

Suitable "lower alkoxycarbonyl" group may include ethoxycarbonyl,propoxycarbonyl, and the like.

Suitable "halogen" may include chloro, bromo, iodo, and the like.

Suitable "aryl" group may include phenyl, tolyl, xylyl, naphthyl, andthe like.

Suitable "protected oxo" group may include bis(substituted-oxy) such asdi(lower)alkoxy (e.g. dimethoxy, diethoxy, dipropoxy, etc.), loweralkylenedioxy (e.g. ethylenedioxy, trimethylenedioxy, propylenedioxy,tetramethylenedioxy, hexamethylenedioxy, etc.), and the like.

Particularly, the preferred embodiments of the terms "R¹ ", "R² " and"A" of the object compounds (I) are as follows.

The formula: R¹ --A-- is a group of the formula: ##STR20## in which R¹is aminothiazolyl which may have halogen (more preferably2-aminothiazol-4-yl, 2-aminothiazol-5-yl, 2-amino-5-halothiazol-4-yl, or4-aminothiazol-2-yl), aminothiadiazolyl (more preferably5-amino-1,2,4-thiadiazol-3-yl), aminooxadiazolyl (more preferably5-amino-1,2,4-oxadiazol-3-yl), aminopyridyl (more preferably6-aminopyridin-2-yl), aminopyrimidinyl (more preferably4-aminopyrimidin-2-yl), acylaminothiazolyl which may have halogen [morepreferably 2-loweralkanamidothiazol-4-yl (e.g. 2-formamidothiazol-4-yl,etc.), 4-loweralkoxycarbonylaminothiazol-2-yl (e.g.4-tert-butoxycarbonylaminothiazol-2-yl, etc.)],di(lower)alkylaminomethyleneaminothiadiazolyl [more preferably5-di(lower)alkylaminomethyleneamino-1,2,4-thiadiazol-3-yl (e.g.5-dimethylaminomethyleneamino-1,2,4-thiadiazol-3-yl, etc.)],di(lower)alkylaminomethyleneaminooxadiazolyl [more preferably5-di(lower)-alkylaminomethyleneamino-1,2,4-oxadiazol-3-yl (e.g.5-dimethylaminomethyleneamino-1,2,4-oxadiazol-3-yl, etc.)] oracylaminopyridyl [more preferably 6-lower alkanamidopyridin-2-yl(e.g.6-formamidopyridin-2-yl, etc.)],

R⁴ is cyclo(lower)alkenyl (e.g. cyclopentenyl, cyclohyexenyl, etc.),lower alkynyl (e.g. propargyl, etc.), lower alkenyl (e.g. allyl, etc.),carboxy(lower)alkenyl (e.g. 3-carboxyallyl, etc.), esterifiedcarboxy(lower)alkenyl [more preferably loweralkoxycarbonyl(lower)alkenyl (e.g. 3-tert-butoxycarbonylallyl, etc.)],lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, pentyl,hexyl, etc.), carboxy(lower)alkyl (e.g. carboxymethyl, 1-carboxyethyl,2-carboxyethyl, 3-carboxypropyl, 1-carboxy-1-methylethyl, etc.),esterified carboxy(lower)alkyl [more preferably loweralkoxycarbonyl(lower)alkyl (e.g. methoxycarbonylmethyl,ethoxycarbonylmethyl, tert-butoxycarbonylmethyl,1-tert-butoxycarbonylethyl, 3-tert-butoxycarbonylpropyl,1-tert-butoxycarbonyl-1-methylethyl, etc.), loweralkanoyloxy(lower)alkoxycarbonyl(lower)alkyl (e.g.acetoxymethoxycarbonylmethyl, pivaloyloxymethoxycarbonylmethyl,hexanoyloxymethoxycarbonylmethyl, etc.), amino- andcarboxy-substituted-loweralkoxycarbonyl(lower)alkyl (e.g.2-amino-2-carboxyethoxycarbonylmethyl, etc.), lower alkoxycarbonylamino-and mono- or di- or triphenyl(lower)alkoxycarbonyl-substituted-loweralkoxycarbonyl(lower)alkyl (e.g.2-tert-butoxycarbonylamino-2-benzhydryloxycarbonylethoxycarbonylmethyl,etc.)], amino- and carboxy-substituted-lower alkyl (e.g.3-amino-3-carboxypropyl, etc.), acylamino- and esterifiedcarboxy-substituted-lower alkyl [more preferably loweralkoxycarbonylamino- and mono- or di- ortriphenyl(lower)alkoxycarbonyl-substituted-lower alkyl (e.g.3-tertbutoxycarbonylamino-3-benzhydryloxycarbonylpropyl, etc.)],cyano(lower)alkyl (e.g. cyanomethyl, cyanoethyl, etc.),phosphono(lower)alkyl (more preferably phosphonomethyl, phosphonoethyl,etc.), esterified phosphono(lower)-alkyl [more preferablyO,O-dialkylphosphono(lower)alkyl (e.g. O,O-dimethylphosphonomethyl,O,O-diethylphosphonomethyl, etc.)] or pyridyl(lower)alkyl (e.g. 2- or3-pyridylmethyl, etc.); or

the formula: R¹ --A-- is one, in which

R¹ is aminothiazolyl (more preferably 2-aminothiazol-4-yl),aminothiadiazolyl (more preferably 5-amino-1,2,4-thiadiazol-3-yl,5-amino-1,3,4-thiadiazol-2-yl), aminooxadiazolyl (more preferably5-amino-1,2,4-oradiazol-3-yl), aminotetrazolyl (more preferably5-amino-2H-tetrazol-2-yl), acylaminothiazolyl [more preferably 2-loweralkanamidothiazol-4-yl (e.g. 2-formamidothiazol-4-yl, etc.), 2-loweralkanesulfonamidothiazol-4-yl (e.g. 2-methanesulfonamidothiazol-4-yl,etc.), 2-trihalo(lower)alkanamidothiazol-4-yl (e.g.2-trifluoroacetamidothiazol-4-yl, etc.) or 2-amidinothiazol-4-yl], mono-or di- or triphenyl(lower)alkylaminothiadiazolyl (more preferably5-tritylamino-1,2,4-thiadiazol-3-yl,5-tritylamino-1,3,4-thiadiazol-2-yl, etc.), mono- or di- ortriphenyl(lower)alkylaminotetrazolyl (more preferably5-tritylamino-2H-tetrazol-2-yl), or a group of the formula: ##STR21##wherein R³ is lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl,pentyl, hexyl, etc.),

A is methylene, aminomethylene, acylaminomethylene [more preferablylower alkoxycarbonylaminomethylene (e.g.tert-butoxycarbonylaminomethylene, etc.)], hydroxymethylene or carbonyl.

The term "R² " is carboxy or esterified carboxy group [more preferablymono- or di- or triphenyl(lower)-alkoxycarbonyl (e.g.benzhydryloxycarbonyl, etc.), lower alkanoyloxy(lower)alkoxycarbonyl(e.g. acetoxymethoxycarbonyl, propionyloxymethoxycarbonyl,isobutyryloxymethoxycarbonyl, pivaloyloxymethoxycarbonyl,hexanoyloxymethoxycarbonyl, 1-acetoxypropoxycarbonyl, etc.), amino andcarboxy-substituted lower alkoxycarbonyl (e.g.2-amino-2-carboxyethoxycarbonyl, etc.), lower alkoxycarbonylamino- andmono or di- ortriphenyl(lower)alkoxycarbonyl-substituted-(lower)alkoxycarbonyl (e.g.2-tert-butoxycarbonylamino-2-benzhydryloxycarbonylethoxycarbonyl, etc.),phthalidyl (e.g. phthalid-3-yl, etc.)].

Suitable intramolecular or intermolecular quaternary salt of the objectcompound (I) may include

7-[2-(2-aminothiazol-4-yl)-2-{(1-methyl-3-pyridinio)-methoxyimino}acetamido]-3-vinyl-3-cephem-4-carboxylate,

7-[2-(2-aminothiazol-4-yl)-2-{(1-methyl-2-pyridinio)-methoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate,

1-methyl-3-[1-(2-aminothiazol-4-yl)-1-{N-(4-benzhydryloxycarbonyl-3-vinyl-3-cephem-7-yl)carbamoylmethyleneaminooxymethyl]pyridiniummethylsulfate,

1-methyl-2-[1-(2-aminothiazol-4-yl)-1-{N-(4-benzhydryloxycarbonyl-3-vinyl-3-cephem-7-yl)carbamoyl}-methyleneaminooxymethyl]pyridiniummethylsulfate.

The processes 1 to 13 for the preparation of the object compounds (I) ofthe present invention are explained in detail in the following.

(1) Process 1

The compounds (I) or a salt thereof can be prepared by reacting thecompound (II) or its reactive derivative at the amino group or a saltthereof with the compound (III) or its reactive derivative at thecarboxy group or a salt thereof.

Suitable salts of the starting compounds (II) and (III) may include thesame ones as illustrated for the compounds (I).

Suitable reactive derivative at the amino group of the compound (II) mayinclude a conventional one, for example, a silyl derivative formed bythe reaction of the compound (II) with a silyl compound such asbis(trimethylsilyl)acetamide, trimethylsilylacetamide, etc.; isocyanate;isothiocyanate; Schiff's base or its tautomeric enamine type isomerformed by the reaction of the amino group with a carbonyl compound suchas an aldehyde compound (e.g. acetaldehyde, isopentaldehyde,benzaldehyde, salicylaldehyde, phenylacetaldehyde, p-nitrobenzaldehyde,m-chlorobenzaldehyde, p-chlorobenzaldehyde, hydroxynaphthoaldehyde,furfural, thiophenecarboaldehyde, etc.) or a ketone compound (e.g.acetone, methyl ethyl ketone, methyl isobutyl ketone, acetylacetone,ethyl acetoacetate, etc.), and the like.

Suitable reactive derivative of the compound (III) may include, forexample, an acid halide, an acid anhydride, an activated amide, anactivated ester, and the like, and preferably an acid chloride and acidbromide; a mixed acid anhydride with an acid such as substitutedphosphoric acid (e.g. dialkylphosphoric acid, phenylphosphoric acid,diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoricacid, etc.), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid,sulfuric acid, alkyl carbonate (e.g. methyl carbonate, ethyl carbonate,propyl carbonate, etc.), aliphatic carboxylic acid (e.g. pivalic acid,pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroaceticacid, etc.), aromatic carboxylic acid (e.g. benzoic acid, etc.); asymmetrical acid anhydride; an activated acid amide with a heterocycliccompound containing imino function such as imidazole, 4-substitutedimidazole, dimethylpyrazole, triazole or tetrazole; an activated ester(e.g. p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenylester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenylester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester,carboxymethyl thioester, pyridyl ester, piperidinyl ester, 8-quinolylthioester, or an ester with a N-hydroxy compound such asN,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone,N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazole,1-hydroxy-6-chlorobenzotriazole, etc.), and the like.

The suitable reactive derivative can optionally be selected from theabove according to the kinds of the compounds (II) and (III) to be usedpractically.

This reaction can be carried out in the presence of an organic orinorganic base such as alkali metal (e.g. lithium, sodium, potassiumetc.), alkaline earth metal (e.g. calcium, etc.), alkali metal hydride(e.g. sodium hydride, etc.), alkaline earth metal hydride (e.g. calciumhydride, etc.), alkali metal hydroxide (e.g. sodium hydroxide, potassiumhydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate,potassium carbonate, etc.), alkali metal bicarbonate (e.g. sodiumbicarbonate, potassium bicarbonate, etc.), alkali metal alkoxide (e.g.sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.),alkali metal alkanoic acid (e.g. sodium acetate, etc.), trialkylamine(e.g. triethylamine, etc.), pyridine compound (e.g. pyridine, lutidine,picoline, etc.), quinoline, and the like.

In case that the compound (III) is used in a form of the free acid or asalt in this reaction, the reaction is preferably carried out in thepresence of a condensing agent such as a carbodiimide compound [e.g.N,N'-dicyclohexylcarbodiimide,N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide,N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide,N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, etc.], a keteniminecompound (e.g. N,N'-carbonylbis(2-methylimidazole),pentamethyleneketene-N-cyclohexylimine,diphenylketene-N-cyclohexylimine, etc.); an olefinic or acetylenic ethercompounds (e.g. ethoxyacetylene, β-chlorovinylethyl ether), a sulfonicacid ester of N-hydroxybenzotriazole derivative [e.g.1-(4-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole, etc.], acombination of trialkylphosphite or triphenylphosphine and carbontetrachloride, disulfide or diazenedicarboxylate (e.g. diethyldiazenedicarboxylate, etc.), a phosphorus compound (e.g. ethylpolyphosphate, isopropyl polyphosphate, phosphoryl chloride, phosphorustrichloride, etc.), thionyl chloride, oxalyl chloride,N-ethylbenzisoxazolium salt, N-ethyl-5-phenylisoxazolium-3-sulfonate, areagent (referred to as so-called "Vilsmeier reagent") formed by thereaction of an amide compound such as N,N-di(lower)alkylformamide (e.g.dimethylformamide, etc.), N-methylformamide or the like with a halogencompound such as thionyl chloride, phosphoryl chloride, phosgene or thelike.

The reaction is usually carried out in a conventional solvent which doesnot adversely influence the reaction such as water, acetone, dioxane,acetonitrile, chloroform, benzene, methylene chloride, ethylenechloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide,pyridine, hexamethylphosphoramide, etc., or a mixture thereof.

Among these solvents, hydrophilic solvents may be used in a mixture withwater.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to warming.

The present invention includes, within the scope thereof, in case thatthe reaction is carried out in the presence of Vilsmeier reagentmentioned above, the amino group for R¹ in the starting compound (III)is occasionally transformed into a(N,N-di(lower)-alkylaminomethylene)amino group during the reaction.

(2) Process 2

The compound (I-b) or a salt thereof can be prepared by subjecting thecompound (I-a) or a salt thereof to removal reaction of theamino-protective group in R_(a) ¹.

Suitable method for this removal reaction may include conventional onesuch as hydrolysis, reduction, combined methods comprisingiminohalogenation and then iminoetherification, followed by hydrolysis,if necessary, and the like.

(i) For hydrolysis

Hydrolysis is preferably carried out in the presence of an acid.

Suitable acid may be an inorganic acid (e.g. hydrochloric acid,hydrobromic acid, sulfuric acid, etc.), an organic acid (e.g. formicacid, acetic acid, trifluoroacetic acid, propionic acid, methanesulfonicacid, benzenesulfonic acid, p-toluenesulfonic acid, etc.), an acidicion-exchange resin and the like. In case that the organic acid such astrifluoroacetic acid and p-toluenesulfonic acid is used in thisreaction, the reaction is preferably carried out in the presence ofcation trapping agents (e.g. anisole, etc.).

The acid suitable for this hydrolysis can be selected according to thekinds of the protective group to be removed, for example, thishydrolysis can preferably be applied to the amino-protective group forR_(a) ¹ such as substituted or unsubstituted lower alkoxycarbonyl,substituted or unsubstituted lower alkanoyl.

The hydrolysis is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as water, methanol,ethanol, propanol, tert-butyl alcohol, tetrahydrofuran,N,N-dimethylformamide, dioxane or a mixture thereof, and further theabove-mentioned acids can also be used as a solvent when they are inliquid.

The reaction temperature of this hydrolysis is not critical, and thereaction is usually carried out under cooling to at somewhat elevatedtemperature.

(ii) For Reduction

Reduction is carried out in a conventional manner, including chemicalreduction and catalytic reduction.

Suitable reducing agents to be used in chemical reduction are acombination of a metal (e.g. tin, zinc, iron, etc.) or metallic compound(e.g. chromium, chloride, chromium acetate, etc.) and an organic orinorganic acid (e.g. formic acid, acetic acid, propionic acid,trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid,hydrobromic acid, etc.).

Suitable catalysts to be used in catalytic reduction are conventionalones such as platinum catalysts (e.g. platinum plate, spongy platinum,platinum black, colloidal platinum, platinum oxide, platinum wire,etc.), palladium catalysts (e.g. spongy palladium, palladium black,palladium oxide, palladium on carbon, colloidal palladium, palladium onbarium sulfate, palladium on barium carbonate, etc.), nickel catalysts(e.g. reduced nickel, nickel oxide, Raney nickel, etc.), cobaltcatalysts (e.g. reduced cobalt, Raney cobalt, etc.), iron catalysts(e.g. reduced iron, Raney iron, etc.), copper catalysts (e.g. reducedcopper, Raney copper, Ullman copper, etc.) and the like.

The reduction manner can be selected according to the kinds of theprotective group to be removed, for example, the chemical reduction canpreferably be applied to the amino-protective group for R_(a) ¹ such ashalo(lower)alkoxycarbonyl and the like, and catalytic reduction canpreferably be applied to that such as substituted or unsubstitutedar(lower)alkoxycarbonyl, and the like.

The reduction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as water, methanol,ethanol, propanol, N,N-dimethylformamide, or a mixture thereof.Additionally, in case that the above-mentioned acids to be used inchemical reduction are in liquid, they can also be used as a solvent.Further, a suitable solvent to be used in catalytic reduction may be theabove-mentioned solvent, and other conventional solvent such as diethylether, dioxane, tetrahydrofuran, etc., or a mixture thereof.

The reaction temperature of this reduction is not critical and thereaction is usually carried out under cooling to warming. (iii) Forcombined methods comprising iminohalogenation (the first step) and theniminoetherification (the 2nd step), followed by hydrolysis (the laststep), if necessary:

The first and second steps of this method are preferably carried out inan anhydrous solvent. Suitable solvent for the first step (i.e.iminohalogenation) is an aprotic solvent such as methylene chloride,chloroform, diethyl ether, tetrahydrofuran, dioxane, etc., and for thesecond step (i.e. iminoetherification) is usually the same as those inthe above first step. These two steps are usually conducted undercooling to at ambient temperature. These two steps and the last step(i.e. hydrolysis step) are most preferably conducted in one-batchsystem.

Suitable iminohalogenating agents include a halogenating agent such asphosphorus halo compound (e.g. phosphorus trichloride, phosphoruspentachloride, phosphorus tribromide, phosphorus pentabromide,phosphorus oxychloride, etc.), thionyl chloride, phosgene, and the like.

Suitable iminoetherifying agent may be an alcohol such as an alkanol(e.g. methanol, ethanol, propanol, isopropanol, butanol, etc.) or thecorresponding alkanol having alkoxy (e.g. 2-methoxyethanol,2-ethoxyethanol, etc.), and alkoxide of metal such as alkali metal,alkaline earth metal (e.g. sodium methoxide, potassium ethoxide,magnesium ethoxide, lithium methoxide, etc.), and the like.

Thus obtained reaction product is, if necessary, hydrolyzed in aconventional manner. The hydrolysis is preferably carried out at ambienttemperature to under cooling, and proceeds simply pouring the reactionmixture into water or a hydrophilic solvent such as alcohol (e.g.methanol, ethanol, etc.) moistened or admixed with water, and ifnecessary, with addition of an acid or base.

Suitable acid may include the same ones as those given in theexplanation of Hydrolysis mentioned in the above item (i), and suitablebase may include the same ones as those given in the explanation ofProcess 1.

The methods thus explained may be selected depending upon the kind ofthe protective groups to be removed.

The present invention includes, within the scope of the invention casesthat the protected amino group and/or the protected carboxy group in R²and A are transformed into free amino group and/or free carboxy group,respectively during the reaction.

(3) Process 3

The compound (I-d) or a salt thereof can be prepared by subjecting thecompound (I-c) or a salt thereof to removal reaction of thecarboxy-protective group for R_(a) ².

This reaction is carried out by a conventional method such ashydrolysis, reduction, and the like.

The method of hydrolysis and reduction, and the reaction conditions(e.g. reaction temperature, solvent, etc.) are substantially the same asthose illustrated for the removal reaction of the amino-protective groupof the compound (I-a) in Process 2, and therefore are to be referred tosaid explanation.

The present invention includes, within the scope of the invention, casesthat the protected amino group in R¹ and A and/or the protected carboxygroup in A are transformed into free amino group(s) and/or a freecarboxy group, respectively during the reaction.

(4) Process 4

The compound (I-c) or a salt thereof can be prepared by introducing acarboxy-protective group into the compound (I-d) or a salt thereof.

The introducing agent of a carboxy-protective group to be used in thisreaction may include a conventional esterifying agent such as an alcoholor its reactive equivalent (e.g. halide, sulfonate, sulfate, diazocompound, etc.), and the like.

The reaction can also be carried out in the presence of a base, andsuitable examples thereof are the same as those given in the explanationof Process 1, and can preferably be carried out in the presence of metaliodide (e.g. sodium iodide, etc.).

This reaction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as N,N-dimethylformamide,tetrahydrofuran, dioxane, methanol, ethanol, etc., or a mixture thereof.

The reaction temperature is not critical, and the reaction is usuallycarried out under cooling to at somewhat elevated temperature.

In case that the alcohol is used as the introducing agent of acarboxy-protective group, the reaction can be carried out in thepresence of a condensing agent as illustrated in Process 1.

The present invention includes, within the scope thereof, the case thatthe carboxy-protective group is occasionally introduced into the carboxygroup in A of the compound (I-d) during the reaction.

(5) Process 5

The compound (I-e) or a salt thereof can be prepared by reacting thecompound (IV) or a salt thereof with the compound (V).

Suitable salts of the starting compound (IV) may include the same saltswith a base for the compounds (I).

This reaction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as ethyl acetate,methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran,dioxane, water, etc., or a mixture thereof.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to warming.

(6) Process 6

The compound (I-g) or a salt thereof can be prepared by subjecting thecompound (I-f) or a salt thereof to removal reaction of thecarboxy-protective group or the phosphono-protective group in A¹.

This reaction is carried out by a conventional method such ashydrolysis, reduction, and the like.

The method of hydrolysis and reduction, and the reaction conditions(e.g. reaction temperature, solvent, etc.) are substantially the same asthose illustrated for the removal reaction of the amino-protective groupof the compound (I-a) in Process 2, and therefore are to be referred tosaid explanation.

Further, for removal reaction of the phosphono-protective group, thereaction can also be carried out by reacting the compound (I-f) withtrialkylsilyl halide such as trimethylsilyl chloride, trimethylsilylbromide, trimethylsilyl iodide, and the like.

The present invention includes, within the scope thereof, cases that theprotected amino group in R¹ and R², and/or the protected carboxy groupin R² are transformed into free amino group and/or free carboxy group,respectively during the reaction.

(7) Process 7

The compound (I) or a salt thereof can be prepared by reacting thecompound (VI) or a salt thereof with formaldehyde.

Suitable salts of the compound (VI) may include the same ones asexemplified for the compounds (I).

This reaction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as tetrahydrofuran,dioxane, etc., or a mixture thereof.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to somewhat elevated temperature.

(8) Process 8

The compound (I-i) or a salt thereof can be prepared by subjecting thecompound (I-h) or a salt thereof to removal reaction of the amino- andcarboxy-protective groups in R_(b) ².

This reaction is carried out by a conventional method such ashydrolysis, reduction, and the like.

The method of hydrolysis and reduction, and the reaction conditions(e.g. reaction temperature, solvent, etc.) are substantially the same asthose illustrated for removal reaction of the amino-protective group ofthe compound (I-a) in Process 2, and therefore are to be referred tosaid explanation.

In this reaction, the amino- and carboxy-protective groups can beremoved separately or at a time.

The present invention includes, within the scope thereof, cases that theprotected amino group in R¹ and A and/or the protected carboxy group inA are transformed into free amino group and/or free carboxy group,respectively during the reaction.

(9) Process 9

The compound (I-k) or a salt thereof can be prepared by subjecting thecompound (I-j) or a salt thereof to removal reaction of the amino- andcarboxy-protective groups in A³.

This reaction is carried out by a conventional method such ashydrolysis, reduction, and the like.

The method of hydrolysis and reduction, and the reaction conditions(e.g. reaction temperature, solvent, etc.) are substantially the same asthose illustrated for removal reaction of the amino-protective group ofthe compound (I-a) in Process 2, and therefore are to be referred tosaid explanation.

In this reaction, the amino- and carboxy-protective groups can beremoved separately or at a time.

The present invention includes, within the scope thereof, cases that theprotected amino group in R¹ and R² and/or the protected carboxy group inR² are transformed into free amino group and/or free carboxy group,respectively during the reaction.

(10) Process 10

The compound (I-f) or a salt thereof can be prepared by introducing acarboxy-protective group or a phosphono-protective group into thecompound (I-g) or a salt thereof.

This reaction is carried out by substantially the same method as thatillustrated for introducing the carboxy-protective group into thecompound (I-d) in Process 4, and therefore, the reaction conditions(e.g. reaction temperature, solvent, etc.) are to be referred to saidexplanation.

The present invention includes, within the scope thereof, case that thecarboxy group for R² is transformed into the protected carboxy groupduring the reaction.

(11) Process 11

The compound (I-m) or a salt thereof can be prepared by reacting thecompound (I-l) or a salt thereof with the compound (VII).

This reaction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as tetrahydrofuran,dioxane, water, etc., or a mixture thereof.

The reaction temperature is not critical, and the reaction is usuallycarried out at ambient temperature to under heating.

(12) Process 12

The compound (I-o) or a salt thereof can be prepared by reacting thecompound (I-n) or a salt thereof with a base.

Suitable base used in this Process may include the same ones as thoseexemplified in Process 1.

This reaction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as water, methanol,ethanol, etc., or a mixture thereof.

The reaction temperature is not critical, and the reaction is usuallycarried out under cooling to warming.

(13) Process 13

The compound (I-q) or a salt thereof can be prepared by subjecting thecompound (I-p) or a salt thereof to removal reaction of theamino-protective group in A⁸.

This reaction is carried out by a conventional method such ashydrolysis, reduction, and the like.

The method of hydrolysis and reduction, and the reaction conditions(e.g. reaction temperature, solvent, etc.) are substantially the same asthose illustrated for removal reaction of the amino-protective group ofthe compound (I-a) in Process 2, and therefore are to be referred tosaid explanation.

The present invention includes, within the scope thereof, cases that theprotected amino group in R¹ and R² and/or the protected carboxy group inR² are transformed into free amino group and/or free carboxy group,respectively during the reaction.

(14) Process 14

The compound (I-s) or a salt thereof can be prepared by reducing thecompound (I-r) or a salt thereof.

The reduction can be carried out by a conventional method such asreduction using a reducing agent, catalytic reduction, and the like.

Suitable reducing agent may include a conventional one used forconversion of a carbonyl group to a hydroxymethyl group such as metalborohydride, for example, alkali borohydride (e.g. sodium borohydride,potassium borohyride, sodium cyanoborohydride, etc.), lithium aluminumhydride, etc.; diborane; and the like.

The catalyst to be used in the catalytic reduction may include the sameones as exemplified for the reduction in Process 2.

This reaction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as water, methanol,ethanol, tetrahydrofuran, dioxane; etc., or a mixture thereof.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to warming.

(15) Process 15

The compound (I-t) or a salt thereof can be prepared by reacting thecompound (I-r) or a salt thereof with the compound (VIII) or a saltthereof.

Suitable salts of the compound (VIII) may include the same acid additionsalts as exemplified for the compounds (I).

In this reaction, when the compound (VIII) is used in a salt form, thisreaction can also be carried out in the presence of a base asexemplified in Process 1.

This reaction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as water, methanol,ethanol, propanol, dioxane, tetrahydrofuran, etc., or a mixture thereof.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to warming.

The object compounds (I) obtained according to the Processes 1 to 15 asexplained above can be isolated and purified in a conventional manner,for example, extraction, precipitation, fractional crystallization,recrystallization, chromatography, and the like.

Process ○1 to ○11 for the preparation of the starting compounds areexplained in detail in the following.

Process ○1 -(1)

The compound ( ○1 -b) or a salt thereof can be prepared by reacting thecompound ( ○1 -a) or a salt thereof with the halogenating agent.

Suitable salts of the compounds ( ○1 -a) with ( ○1 -b) may include thesame salt with a base as exemplified for the compounds (I).

Suitable halogenating agent used in this reaction may include one whichcan be applied to conversion of a hydroxy group to halo group such asphosphorus halide (e.g. phosphorus trichloride, phosphoruspentachloride, phosphorus oxychloride, phosphorus tribromide, phosphoruspentabromide, etc.), thionyl halide (e.g. thionyl chloride, etc.),phosgene, and the like.

This reaction is preferably carried out in the presence of a base suchas an organic base given in the explanation of Process 1.

This reaction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as methylene chloride,chloroform, ethylene chloride, tetrahydrofuran, dioxane,N,N-dimethylformamide, etc., or a mixture thereof.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to warming.

Process ○1 -(2)

The compound ( ○1 -c) or a salt thereof can be prepared by reacting thecompound ( ○1 -b) or a salt thereof with a trisubstituted phosphine (IX)of the formula: P(R⁷)₃, wherein R⁷ is as defined above.

Suitable salts of the compound ( ○1 -c) may include the same salt with abase as exemplified for the compounds (I).

This reaction is preferably carried out in the presence of metal halidesuch as alkali metal halide (e.g. sodium iodide, potassium iodide,sodium bromide, etc.), and the like, and in such a case, the halogen forX² of the compound ( ○1 -b) can be replaced with the halo moiety of suchmetal halide in the object compound ( ○1 -c) during the reaction.

This reaction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as N,N-dimethylformamide,dimethylsulfoxide, methylene chloride, tetrahydrofuran, ethyl acetate,etc., or a mixture thereof.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to warming.

Process ( ○1 -(3)

The compound ( ○1 -d) or a salt thereof can be prepared by reacting thecompound ( ○1 -c) or a salt thereof with a base.

Suitable salts of the compound ( ○1 -d) may include the same salt with abase as exemplified for the compounds (I).

Suitable base used in this process are the same as those given in theexplanation of Process 1.

This reaction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as acetone,tetrahydrofuran, water, etc., or a mixture thereof.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to at somewhat elevated temperature.

Process ○1 -(4)

The compound ( ○1 -f) or a salt thereof can be prepared by reacting thecompound ( ○1 -e) or its reactive derivative at the amino group or asalt thereof with the compound (III) or its reactive derivative at thecarboxy group or a salt thereof.

Suitable salts of the compound ( ○1 -e) may include the same ones asexemplified for the compounds (I), and suitable salts of the compounds (○1 -f) may include the same salt with a base as exemplified for thecompounds (I).

Suitable reactive derivative of the compounds ( ○1 -e) may include thesame ones as exemplified for the compounds (II) in Process 1,respectively.

The reaction is substantially the same method as Process 1, andaccordingly, the method, reaction conditions (e.g. reaction temperature,solvent, base, etc.) are to be referred to said explanation.

Process ○2 -(1)

The compound ( ○2 -b) or a salt thereof can be prepared by reacting thecompound ( ○2 -a) or a salt thereof with formaldehyde.

Suitable salts of the compounds ( ○2 -a) and ( ○2 -b) may include thesame ones as exemplified for the compounds (I).

This reaction can be carried out by substantially the same method asthat illustrated for Process 7, and therefore reaction conditions (e.g.reaction temperature, solvent, etc.) are to be referred to saidexplanation.

Process ○2 -(2)

The compound ( ○2 -d) or a salt thereof can be prepared by subjectingthe compound ( ○2 -c) or a salt thereof to removal reaction of thecarboxy-protective group.

Suitable salts of the compounds ( ○2 -c) may include the same acidaddition salts as exmplified for the compounds (I), and suitable saltsof the compound ( ○2 -d) may include the same ones as exemplified forthe same compounds.

This reaction is carried out by a conventional method such ashydrolysis, and the like.

The hydrolysis is carried out by substantially the same method as thatillustrated for Process 2, and therefore the method of hydrolysis andthe reaction conditions (e.g. reaction temperature, solvent, etc.) arereferred to said explanation.

Process ( ○2 -(3)

The compound ( ○2 -f) or a salt thereof can be prepared by reacting thecompound ( ○2 -e) or its reactive derivative at the amino group or asalt thereof with the compound (X) or its reactive derivative at thecarboxy group or a salt thereof.

Suitable salts of the compound ( ○2 -e) may include the same ones asexmplified for the compounds (I), and suitable salts of the compounds (○2 -f) and (X) may include the same salts with a base as exemplified forthe compounds (I).

Suitable reactive derivative at the amino group of the compound ( ○2 -e)and that at the carboxy group of the compound (X) may include the sameones as exemplified for the compounds (II) and (III) in Process 1.

The reaction is substantially the same method as Process 1, andaccordingly, the method, reaction conditions (e.g. reaction temperature,solvent, base, etc.) are to be referred to said explanation.

Process ○2 -(4)

The compound ( ○2 -h) or a salt thereof can be prepared by subjectingthe compound ( ○2 -g) or a salt thereof to removal reaction of theoxo-protective group.

Suitable salts of the compounds ( ○2 -g) and ( ○2 -h) may include thesame salt with a base as exemplified for the compounds (I).

This reaction is carried out by a conventional method such ashydrolysis, and the like.

The method of hydrolysis, and the reaction conditions (e.g. reactiontemperature, solvent, etc.) are substantially the same as thoseillustrated for Process 2, and therefore are to be referred to saidexplanation.

Process ( ○3 -(1)

The compound ( ○3 -b) or a salt thereof can be prepared by reacting thecompound ( ○3 -a) or a reactive derivative at the carboxy group or asalt thereof with lower alkanol substituted by protected amino andprotected carboxy groups (XI).

Suitable salts of the compounds ( ○3 -a) and ( ○3 -b) may include thesame ones as exemplified for the compounds (I).

Suitable reactive derivative at the carboxy group of the compound ( ○3-a) may include the same ones as the compound (III) in Process 1.

This reaction is carried out by substantially the same method as thatillustrated for Process 4, and therefore, the reaction conditions (e.g.reaction temperature, solvent, etc.) are to be referred to saidexplanation.

Process ( ○3 -(2)

The compound ( ○3 -c) or a salt thereof can be prepared by subjectingthe compound ( ○3 -b) or a salt thereof to removal reaction of theamino-protective group in R_(D) '.

Suitable salt of the compound ( ○3 -c) may include the same ones asexemplified for the compounds (I).

This reaction is carried out by substantially the same method as thatillustrated for Process 2, and therefore, the reaction conditions (e.g.reaction temperature, solvent, etc.) are to be referred to saidexplanation.

Process ( ○4 -(1) Step 1

The compound ( ○4 -b) or a salt thereof can be prepared by reacting thecompound ( ○4 -a) or a salt thereof with hydroxylamine or a saltthereof.

Suitable salt of hydroxylamine may include the same acid addition saltas exemplified for the compounds (I).

Suitable salts of the compounds ( ○4 -a) and ( ○4 -b) may include thesame salt with a base as exemplified for the compounds (I).

In case that the salt of hydroxylamine is used as the reagent, thereaction can usually be carried out in the presence of a base such asthose illustrated in Process 1.

The reaction is usually carried out in a conventional solvent which doesnot adversely influence the reaction such as methanol, ethanol, etc., ora mixture thereof.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to warming.

Step 2

The compound ( ○4 -c) or a salt thereof can be prepared by reacting thecompound ( ○4 -b) or a salt thereof with the compound (XII) or itsreactive derivative at the carboxy group or a salt thereof.

Suitable salt of the compounds ( ○4 -c) and (XII) may include the samesalt with a base as exemplified for the compounds (I).

Suitable reactive derivative at the carboxy group of the compound (XII)may include the same ones as illustrated for the compound (III) inProcess 1.

This reaction is carried out by substantially the same method as Process1, and therefore, the reaction conditions (e.g. reaction temperature,solvent, etc.) are to be referred to said explanation.

Process ○4 -(2)

The compound ( ○4 -d) or a salt thereof can be prepared by reacting thecompound ( ○4 -c) or a salt thereof with ammonia.

Suitable salts of the compound ( ○4 -d) may include the same ones asexemplified for the compounds (I).

This reaction can be carried out in the absence of or in the presence ofa solvent which does not adversely influence the reaction such asdioxane, etc., and the reaction is usually carried out in the absence ofa solvent.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to warming.

In case that the compound ( ○4 -d) is one of the geometrical isomerssuch as anti isomer, it can be transformed into the other isomer such assyn isomer in a conventional manner, for example, by treating an acidsuch as those illustrated in Process 2.

Process ○4 -(3)

The compound ( ○4 -f) or a salt thereof can be prepared by reacting thecompound ( ○4 -e) or a salt thereof with the compound (XIII) or a saltthereof.

Suitable salts of the compounds ( ○4 -e), ( ○4 -f) and (XIII) mayinclude the same salt with a base as exemplified for the compounds (I).

This reaction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as diethyl ether,diisopropyl ether, etc., or a mixture thereof.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to warming.

Process ○4 -(4)

The compound ( ○4 -g) or a salt thereof can be prepared by subjectingthe compound ( ○4 -f) or a salt thereof to azidation (the first step)and then, subjecting the resultant compound to a thermal degradationreaction (the second step), followed by treating the resultant compoundwith the alcohol (the last step).

Suitable salts of the compound ( ○4 -g) may include the same salt with abase as exemplified for the compounds (I).

(i) As to the first step:

Suitable azidating agent may include hydrazoic acid or its reactivederivative such as sodium azide, potassium azide, calcium azide,diphenylphosphorous azide and the like.

This reaction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as alcohol mentionedbelow, tetrahydrofuran, dichloromethane, diethyl ether, or a mixturethereof, and the like.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to at ambient temperature.

(ii) As to the second step:

This reaction can be carried out by heating the resulting compoundobtained in the first step. This reaction is usually carried out in aconventional solvent as mentioned in the first step.

(iii) As to the last step:

This reaction can be carried out by adding alcohol.

Suitable alcohol may include lower alkanol (e.g. methanol, ethanol,propanol, butanol, tert-butanol, etc.), ar(lower)alkanol (e.g. benzylalcohol, benzhydryl alcohol, etc.), and the like.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to warming.

A chain of these steps mentioned above can also be carried out by onepot.

Process ○4 -(5)

The compound ( ○4 -h) or a salt thereof can be prepared by reacting thecompound ( ○4 -g) or a salt thereof with an oxidizing agent.

Suitable salts of the compound ( ○4 -h) may include the same salt with abase as exemplified for the compounds (I).

Suitable oxidizing agent may include one which is applied for thetransformation of so-called activated methylene group into carbonylgroup such as selenium dioxide or the like.

The present reaction is usually carried out in a conventional solventwhich does not adversely influence the reaction such as tetrahydrofuran,dioxane, etc., or a mixture thereof.

The reaction temperature is not critical and the reaction is preferablycarried out under warming to heating.

Process ○4 -(6)

The compound ( ○4 -i) or a salt thereof can be prepared by reacting thecompound ( ○4 -h) or a salt thereof with the compound (VIII) or a saltthereof.

Suitable salts of the compound ( ○4 -i) may include the same salt with abase as exemplified for the compounds (I), and suitable salts of thecompound (VIII) may include the same acid addition salt as exemplifiedfor the same compounds.

This reaction is carried out by substantially the same method as that ofProcess 15, and therefore the reaction conditions (e.g. reactiontemperature, solvent, base, etc.) are to be referred to saidexplanation.

Process ○4 -(7)

The compound ( ○4 -k) or a salt thereof can be prepared by subjectingthe compound ( ○4 -j) or a salt thereof to removal reaction of thecarboxy-protective group for R^(i).

Suitable salts of the compound ( ○4 -k) may include the same ones asexemplified for the compounds (I), and suitable salts of the compound (○4 -j) may include the same acid addition salt as exemplified for thesame compounds.

This reaction is carried out by a conventional method such ashydrolysis, reduction, and the like.

The method of hydrolysis and reduction, and the reaction conditions(e.g. reaction temperature, solvent, etc.) are substantially the same asthose illustrated for Process 2, and therefore are to be referred tosaid explanation.

Process 5

The compound ( ○5 -b) or a salt thereof can be prepared by reacting thecompound ( ○5 -a) or a salt thereof with the compound (XV) or a saltthereof.

Suitable salts of the compounds ( ○5 -a), ( ○5 -b) and (XV) may includethe same ones as exemplified for the compounds (I).

This reaction is carried out by substantially the same method as that ofProcess 15, and therefore the reaction conditions (e.g. reactiontemperature, solvent, base, etc.) are to be referred to saidexplanation.

Process 6

The compound ( ○6 -b) or a salt thereof can be prepared by reacting thecompound ( ○6 -a) or a salt thereof with the compound (XVI) or a saltthereof.

Suitable salts of the compounds ( ○6 -a), ( ○6 -b) and (XVI) may includethe same ones as exemplified for the compounds (I).

This reaction is carried out by substantially the same method as that ofProcess 15, and therefore the reaction conditions (e.g. reactiontemperature, solvent, base, etc.) are to be referred to saidexplanation.

Process ○7 -(1)

The compound ( ○7 -b) can be prepared by reacting the compound ( ○7 -a)or a reactive derivative at the hydroxy group with N-hydroxyphthalimideor a salt thereof.

Suitable salts of N-hydroxyphthalimide may include the alkali metal saltas exemplified for the compounds (I).

Suitable reactive derivative at the hydroxy group may include halidesuch as chloride, bromide, and the like.

This reaction is preferably carried out in the presence of a base asexemplified in Process 1.

In case that the compound ( ○7 -a) is used in a free form, the reactioncan usually be carried out in the presence of a condensing agent asexemplified in Process 1.

This reaction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as tetrahydrofuran,N,N-dimethylformamide, acetonitrile, etc., or a mixture thereof.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to heating.

Process ( ○7 -(2)

The compound ( ○7 -c) or a salt thereof can be prepared by subjectingthe compound ( ○7 -b) to removal reaction of the phthaloyl group.

Suitable salt of the compound ( ○7 -c) may include the same acidaddition salt as exemplified for the compounds (I).

This reaction is carried out by a conventional method such ashydrolysis, and the like.

The method of hydrolysis, and the reaction conditions (e.g. reactiontemperature, solvent, etc.) are substantially the same as thoseillustrated for Process 2, and therefore are to be referred to saidexplanation.

Process ○8

The compound ( ○8 -b) or a salt thereof can be prepared by subjectingthe compound ( ○8 -a) to removal reaction of the acyl group.

Suitable salts of the compound ( ○8 -b) may include the same acidaddition salts as exemplified for the compounds (I).

This reaction is usually carried out by combined methods comprisingiminohalogenation and the iminoetherification, followed by hydrolysis,if necessary.

These combined methods and reaction conditions (e.g. reactiontemperature, solvent, etc.) are substantially the same as thoseillustrated for Process 2, and therefore are to be referred to saidexplanation.

Process ○9 Step 1

The compound ( ○9 -b) or a salt thereof can be prepared by subjectingthe compound ( ○9 -a) or a salt thereof to removal reaction of the acylgroup.

Suitable salts of the compound ( ○9 -a) may include the same salt with abase as exemplified for the compounds (I), and suitable salts of thecompound ( ○9 -b) may include the same ones as exemplified for the samecompounds (I).

This reaction can be carried out by combined methods comprisingiminohalogenation and then iminoetherification, followed by hydrolysis,if necessary.

The combined methods and the reaction conditions (e.g. reactiontemperature, solvent, etc.) are substantially the same as thoseillustrated for Process 2, and therefore are to be referred to saidexplanation.

Step 2

The compound ( ○9 -c) or a salt thereof can be prepared by reacting thecompound ( ○9 -b) or a salt thereof with the compound (XVII) of theformula: R⁸ --CHO, wherein R⁸ is as defined above.

Suitable salts of the compound ( ○9 -c) may include the same salt with abase as exemplified for the compounds (I).

This reaction is preferably carried out in the presence of a dehydratingagent such as molecular sieve, and the like.

This reaction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as N,N-dimethylformamide,etc.

The reaction temperature is not critical and the reaction is usuallycarried out at ambient temperature to under heating.

Process ○10

The compound ( ○10 -b) or a salt thereof can be prepared by reducing thecompound ( ○10 -a) or a salt thereof.

Suitable salts of the compounds ( ○10 -a) and ( ○10 -b) may include thesame ones as exemplified for the compounds (I).

This reaction is carried out by a conventional method such as catalyticreduction, using a reducing agent, and the like.

The method of catalytic reduction and the reaction conditions (e.g.reaction temperature, solvent, etc.) are substantially the same as thoseillustrated for Process 2, and therefore are to be referred to saidexplanation.

Further, suitable reducing agent may include borane, diborane, and thelike.

Process ○11 -(1)

The compound ( ○11 -b) or a salt thereof can be prepared by reducing thecompound ( ○11 -a).

Suitable salts of the compound ( ○11 -b) may include the same acidaddition salt as exemplified for the compounds (I).

The reduction can be carried out by a conventional method such aschemical reduction, catalytic reduction, and the like.

The method of chemical reduction and catalytic reduction, and thereaction conditions (e.g. reaction temperature, solvent, etc.) aresubstantially the same as those illustrated for Process 2, and thereforeare to be referred to said explanation.

Process ○11 -(2)

The compound ( ○11 -c) can be prepared by introducing anamino-protective group into the compound ( ○11 -b) or a salt thereof.

The introducing agent of an amino-protective group to be used in thisreaction may include a conventional acylating agent such as thecorresponding acid to the acyl group as aforementioned or its reactivederivative (e.g. acid halide, acid anhydride, etc.), 2-loweralkoxycarbonyloxyimino-2-phenylacetonitrile (e.g.2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile, etc.), alkyl ketonesubstituted by lower alkoxycarbonyl (e.g. lower alkyl acetoacetate, forexample, methyl acetoacetate, etc., etc.), and the like.

This reaction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as water, methanol,ethanol, propanol, tetrahydrofuran, dioxane, etc., or a mixture thereof.

This reaction is preferably carried out in the presence of a base, andsuitable examples thereof are the same as those given in the explanationof Process 1.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to warming.

Process ○11 -(3)

The compound ( ○11 -f) or a salt thereof can be prepared by subjectingthe compound ( ○11 -c) to removal reaction of the carboxy-protectivegroup for R^(i).

Suitable salts of the compound ( ○11 -f) may include the same salt witha base as exemplified for the compounds (I).

The reaction can be carried out by a conventional method such ashydrolysis, reduction, and the like.

The method of hydrolysis and reduction, and the reaction conditions(e.g. reaction temperature, solvent, etc.) are substantially the same asthose illustrated for Process 2, and therefore are to be referred tosaid explanation.

Additionally, hydrolysis can be carried out in the presence of a base,and suitable examples thereof are the same as those in the explanationof Process 1.

Process ○11 -(4)

The compound ( ○11 -e) or a salt thereof can be prepared by subjectingthe compound ( ○11 -d) or a salt thereof to removal reaction of thecarboxy-protective group.

Suitable salts of the compounds ( ○11 -e) may include the same ones asexemplified for the compounds (I), and suitable salts of the compound (○11 -d) may include the same acid addition salt for the same compounds.

This reaction is carried out by a conventional method such ashydrolysis, reduction, and the like.

The method of hydrolysis and reduction, and the reaction conditions (e.greaction temperature, solvent, etc.) are substantially the same as thoseillustrated for the removal reaction of the amino-protective group inProcess 2, and therefore are to be referred to said explanation.Additionally, hydrolysis can be carried out in the presence of a base,and suitable examples thereof are the same as those in the explanationof Process 1.

Process ○11 -(5)

The compound ( ○11 -f) or a salt thereof can be prepared by introducingan amino-protective group into the compound ( ○11 -e) or a salt thereof.

This reaction is substantially the same as Process ○11 -(2), andtherefore, the reaction method and reaction conditions (e.g. reactiontemperature, solvent, etc.) are to be referred to said explanation.

Process ○11 -(6)

The compound ( ○11 -f) or a salt thereof can be prepared by introducingan amino-protective group into the compound ( ○11 -g) or a salt thereof.

Suitable salts of the compound ( ○11 -g) may include the same ones asexemplified for the compounds (I).

This reaction is carried out by substantially the same method as that ofProcess ○11 -(2), and therefore the reaction conditions (e.g. reactiontemperature, solvent, base, etc.) are to be referred to saidexplanation.

The starting compounds thus prepared can be isolated in a conventionalmanner as mentioned for the object compounds of the present invention.

It is to be noted that, in the aforementioned reactions in Processes 1to 15 and ○1 to ○11 or the post-treatment of the reaction mixturetherein, in case that the starting or object compounds possess anoptical and/or geometrical isomer(s), it may occasionally be transformedinto the other optical and/or geometrical isomer(s), and such cases arealso included within the scope of the present invention.

In case that the object compounds (I) have a free carboxy group or freeamino group at the 4th or 7th position thereof, it may be transformedinto its pharmaceutically acceptable salts by a conventional method.

The object compounds (I) and the pharmaceutically acceptable saltsthereof of the present invention are novel and exhibit highantimicrobial activity, inhibiting the growth of a wide variety ofpathogenic microorganisms including Gram-positive and Gram-negativemicroorganisms and are useful as antimicrobial agents, especially fororal administration as shown in the following data.

Now in order to show the utility of the object compounds (I), the testdata on the antimicrobial activity of some representative compounds (I)of this invention are shown in the following. (1) Test 1: in vitroAntimicrobial Activities.

TEST COMPOUNDS

No. 17-[2-(3-Methanesulfonamidophenyl)-D-glycinamido]-3-vinyl-3-cephem-4-carboxylicacid (hereinafter referred to as Compound A)

No. 2 7-[2-(2-Aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (hereinafter referred to as Compound B)

No. 37-[2-(2-Aminothiazol-4-yl)glycolamido]-3-vinyl-3-cephem-4-carboxylicacid (hereinafter referred to as Compound C)

No. 47-[2-(2-Formamidothiazol-5-yl)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (hereinafter referred to as Compound D)

No. 5 7-[2-(2-Aminothiazol-5-yl)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (hereinafter referred to as Compound E)

No. 67-[2-(2-Methanesulfonamidothiazol-5-yl)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (hereinafter referred to as Compound F)

No. 77-[2-(2-Guanidinothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylicacid hydrobromide (hereinafter referred to as Compound G)

No. 8 7-[2-(2-Aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (hereinafter referred to as Compound H)

No. 97-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (hereinafter referred to as Compound I)

No. 107-[2-(2-Aminothiazol-4-yl)-2-ethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (hereinafter referred to as Compound J).

No. 117-[2-(2-Aminothiazol-4-yl)-2-hexyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (hereinafter referred to as Compound K).

No. 127-[2-(2-Aminothiazol-4-yl)-2-(L-2-amino-2-carboxyethoxycarbonylmethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (hereinafter referred to as Compound L)

No. 137-[2-(2-Aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (hereinafter referred to as Compound M)

No. 147-[2-(2-Amino-5-chlorothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (hereinafter referred to as Compound N).

No. 157-[2-(2-Aminothiazol-4-yl)-2-(trans-3-carboxyallyloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (hereinafter referred to as Compound O).

No. 167-[2-(2-Aminothiazol-4-yl)-2-(3-carboxypropoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (hereinafter referred to as Compound P).

TEST METHOD

In vitro Antimicrobial activity was determined by the two-foldagar-plate dilution method as described below.

One loopful of a overnight culture of each test strain in Tripticase-soybroth (approximately 10⁸ viable cells per ml) was streaked on heartinfusion agar (HI-agar) containing graded concentrations ofantimicrobial agents, and the minimal inhibitory concentration (MIC) wasexpressed in term of μg/ml after incubation at 37° C. for 20 hours.

                  Test Results 1                                                  ______________________________________                                        MIC (μg/ml)                                                                          Microorganisms                                                                  Staphylococcus aureus                                                                         Batilus subtilis                                  Test Compounds                                                                            209P JC-1       ATCC 6633                                         ______________________________________                                        A           1.56            0.10                                              B           1.56            1.56                                              C           1.56            0.78                                              D           0.39            0.20                                              E           0.78            0.05                                              F           1.56            0.39                                              G           0.39            0.10                                              H           0.78            0.39                                              J           1.56            0.78                                              K           1.56            0.78                                              ______________________________________                                    

                  Test Results 2                                                  ______________________________________                                        MIC (μg/ml)                                                                           Microorganisms                                                                  Proteus mirabilis                                                                          Proteus mirabilis                                   Test Compounds                                                                             1            18                                                  ______________________________________                                        I            0.05         <0.025                                              L            0.05         0.05                                                M            <0.025       <0.025                                              N            0.20         0.05                                                O            0.10         0.10                                                P            0.10         0.05                                                ______________________________________                                    

                  Test Results 3                                                  ______________________________________                                        MIC (μg/ml)                                                                               Microorganisms                                                                Proteus vulgaris                                               Test Compounds 2                                                              ______________________________________                                        N              0.05                                                           O              <0.025                                                         P              <0.025                                                         ______________________________________                                    

(2) Test 2

Determination of serum levels after oral administration ofanti-microbial agents in rats

Test Compound Compound A TEST ANIMAL

6 weeks old male rats, SD strain, each weighing 160-230 g.

TEST METHOD

The test compound A (100 mg/kg) was given orally to rats which had beenfasted overnight. At specified intervals, the rats were anethetized withchloroform and blood samples were collected from the heart. Theanti-microbial levels in each serum sample were determined by the discmethod using standard solutions prepared with serum from rats.

                  Test Results                                                    ______________________________________                                                 Mean Serum Level (μg/ml)                                          Compound   1 hour  2 hours    4 hours                                                                             6 hours                                   ______________________________________                                        A          38.5    34.9       31.0  28.8                                      ______________________________________                                    

(3) Test 3

Protecting effect in experimental mice infection

Test Compound Compound A TEST ANIMAL

4 weeks old male mice, ICR strain, each weighing 20.0±1.5 g.

TEST METHOD

1.3×10⁴ cells of pathogenic microorganisms, suspended in 2.5% mucin,were intraperitoneally injected. One hour after the injection, CompoundA was orally given. These mice were observed for survival or death for 4days, and the ED₅₀ values were calculated by the probit method.

                  Test Results                                                    ______________________________________                                        Injected Pathogenic                                                                           ED.sub.50 value:mg/mouse                                      Microorganisms  Compound A                                                    ______________________________________                                        Escherichia coli 29                                                                           0.480                                                         ______________________________________                                    

For therapeutic administration, the object compounds (I) and thepharmaceutically acceptable salts thereof of the present invention areused in the form of conventional pharmaceutical preparation whichcontains said compound, as active ingredients, in admixture withpharmaceutically acceptable carriers such as an organic or inorganicsolid or liquid excipient which is suitable for oral, parenteral andexternal administration. The pharmaceutical preparations may be in solidform such as tablet, granule, powder, capsule, or liquid form such assolution, suspension, syrup, emulsion, lemonade and the like.

If needed, there may be included in the above preparations auxiliarysubstances, stabilizing agents, wetting agents and other commonly usedadditives such as lactose, magnesium stearate, terra alba, sucrose, cornstarch, talc, stearic acid, gelatin, agar, pectin, peanut oil, oliveoil, cacao butter, ethylene glycol and the like.

While the dosage of the compounds (I) may vary from and also depend uponthe age, conditions of the patient, a kind of diseases, a kind of thecompounds (I) to be applied, etc. In general, amounts between 1 mg andabout 4,000 mg or even more per day may be administered to a patient. Anaverage single dose of about 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg,2000 mg of the object compounds (I) of the present invention may be usedin treating diseases infected by pathogenic microorganisms.

The following examples are given for the purpose of illustrating thepresent invention.

PREPARATION OF THE STARTING COMPOUNDS PREPARATION 1

To a solution of ethyl 2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetate(syn isomer) (19 g) in methanol (200 ml) were added 50% formic acid (200ml) and zinc (29 g), and the mixture was stirred at 5° to 10° C. for 6hours. After filtration, the reaction mixture was evaporated, followedby dissolving the residue in water (150 ml). The resultant aqueoussolution was adjusted to pH 6.5 with 4N aqueous solution of sodiumhydroxide, followed by addition of ethanol (150 ml),2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile (18.2 g) andtriethylamine (8.0 g). After stirring at ambient temperature for 24hours, the reaction mixture was filtered, followed by removal of theorganic solvent. The remained aqueous solution was washed with ethylacetate, adjusted to pH 4 with 10% hydrochloric acid and then extractedwith ethyl acetate. The extract was washed with an aqueous solution ofsodium chloride, dried over anhydrous magnesium sulfate and evaporatedto dryness under reduced pressure to give a residue, which was washedwith diethyl ether to obtainN-tert-butoxycarbonyl-2-(2-formamidothiazol-4-yl)glycine (3.3 g).

IR (Nujol): 3250, 3180, 1720, 1700, 1670, 1640, 1540, 1510 cm⁻¹.

NMR δppm (DMSO-d₆): 1.40 (9H, s), 5.18 (1H, d, J=8 Hz), 7.17 (1H, s),8.43 (1H, s).

PREPARATION 2

A mixture of 2-(2-aminothiazol-4-yl)glycine ethyl ester (24.2 g) and 2Naqueous solution of sodium hydroxide (7.2 g) in methanol (240 ml) wasstirred at ambient temperature for an hour. After adjusting to pH 7 withconc. hydrochloric acid, water (250 ml), and then2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile (29.5 g) andtriethylamine (18.2 g) were added thereto. After stirring at ambienttemperature for an hour, the reaction mixture was evaporated. Theresultant aqueous solution was washed twice with ethyl acetate, followedby adding ethyl acetate and adjusting to pH 7 with 10% hydrochloricacid. After removal of the insoluble substance by filtration, theaqueous layer was separated out, adjusted to pH 4 with 10% hydrochloricacid and treated with activated charcoal. To the filtrate was addedsodium chloride, followed by stirring under ice-cooling. Theprecipitated solid was collected by filtration and dried to giveN-tert-butoxycarbonyl-2-(2-aminothiazol-4-yl)glycine (10.2 g).

NMR δppm (D₂ O+NaHCO₃): 1.40 (9H, s), 4.90 (1H, s), 6.53 (1H, s).

PREPARATION 3

To a solution of N-tert-butoxycarbonyl-2-(2-aminothiazol-4-yl)glycine(5.5 g) and bis(trimethylsilyl)acetamide (10.6 g) in ethyl acetate (55ml) was added trifluoroacetic anhydride (12.6 g) at -20° C., and themixture was stirred at -15° to -5° C. for an hour. After addition ofethyl acetate (100 ml) and water, the mixture was stirred for a while.To the separated ethyl acetate solution was added water (80 ml),followed by adjusting to pH 7 with a saturated aqueous solution ofsodium bicarbonate. After separating out the aqueous layer, thereto wasadded ethyl acetate, followed by adjusting to pH 2 with 10% hydrochloricacid. The ethyl acetate layer was separated out, washed with an aqueoussolution of sodium chloride, dried over anhydrous magnesium sulfate andthen evaporated to giveN-tert-butoxycarbonyl-2-[2-(2,2,2-trifluoroacetamido)thiazol-4-yl]glycine(3.4 g).

IR (Nujol): 3350, 1720, 1680, 1580, 1520 cm⁻¹.

NMR δppm (DMSO-d₆): 1.40 (9H, s), 5.27 (1H, d, J=8 Hz), 7.27 (1H, s).

PREPARATION 4

Formic acid (8.4 g) was added to acetic anhydride (18.7 g) underice-cooling with stirring, and the stirring was continued at 45° to 50°C. for an hour. To the resultant solution was added2-(2-aminothiazol-5-yl)acetic acid (5.8 g) at ambient temperature, andthe mixture was stirred for 35 minutes. After the reaction mixture wasevaporated to dryness, the residual product was treated with diisopropylether and then collected by filtration to give2-(2-formamidothiazol-5-yl)acetic acid (5.87 g), mp 229° C. (dec.).

I.R. (Nujol): 3200, 1670, 1560, 1530 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.82 (2H, s), 7.29 (1H, s), 8.47 (1H, s), 12.37(1H, broad s).

PREPARATION 5

To a solution of N,N-dimethylformamide (8.8 g) and tetrahydrofuran (230ml) was added dropwise phosphorus oxychloride (18.5 g) at -5° to 0° C.,and the mixture was stirred for a while. To this solution was added2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer) (25.2g) at 3° C., followed by stirring at the same temperature for 40 minutesto prepare the activated acid solution.

On the other hand, a mixture of benzhydryl7-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride (45.1 g) andtrimethylsilylacetamide (104.8 g) in ethyl acetate (400 ml) was stirredat ambient temperature for 20 minutes. To the resultant solution wasadded the activated acid solution prepared before at -40° C. withstirring, and the stirring was continued at -30° to -10° C. for 1.8hours. After addition of water (200 ml), the organic layer was separatedout. The remained aqueous solution was extracted with ethyl acetate, andthis extract and the organic layer were combined and washed with asaturated aqueous solution of sodium bicarbonate and an aqueous solutionof sodium chloride, followed by drying over anhydrous magnesium sulfate.After concentration, the precipitated substance was collected byfiltration to give benzhydryl7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylate(syn isomer) (45.2 g). The filtrate was evaporated to dryness and theresidue was washed with diethyl ether to recover the same product (7.9g). Total yield: 53.1 g.

I.R. (Nujol): 3250, 3160, 3110, 1780, 1720, 1690, 1660, 1630, 1565, 1540cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.70 (2H, broad s), 3.93 (3H, s), 4.47 (2H, broads), 5.30 (1H, d, J=5 Hz), 6.03 (1H, dd, J=5 Hz, 8 Hz), 7.03 (1H, s),7.17-7.73 (11H, m), 8.62 (1H, s), 9.90 (1H, d, J=8 Hz)

PREPARATION 6

To a solution of benzhydryl7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylate(syn isomer) (25.0 g) in ethyl acetate (300 ml) was added a solution oftriphenylphosphine (21.0 g) in tetrahydrofuran (170 ml), and the mixturewas heated under reflux for 10 hours. The precipitated substance wascollected by filtration to give[7-{2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido}-4-benzhydryloxycarbonyl-3-cephem-3-yl]methyl-triphenylphosphoniumchloride (syn isomer) (17.7 g). The remained filtrate was heated underreflux for 10 hours. Similarly, the precipitated substance was collectedby filtration to recover the same product (9.75 g). Further, thisoperation was repeated once to recover the same product (3.3 g). Totalyield: 30.75 g.

I.R. (Nujol): 1780, 1720, 1680, 1590, 1540 cm⁻¹.

PREPARATION 7

[7-{2-(2-Formamidothiazol-4-yl)-2-methoxyiminoacetamido}-4-benzhydryloxycarbonyl-3-cephem-3-yl]methyltriphenylphosphoniumchloride (syn isomer) (5.33 g) was dissolved in a mixture of acetone (60ml) and water (10 ml), and the solution was adjusted to pH 11 with 2Naqueous solution of sodium hydroxide, followed by extraction three timeswith ethyl acetate (100 ml). The extract was washed with an aqueoussolution of sodium chloride, dried over anhydrous magnesium sulfate andthen evaporated to dryness to give a residue, which was pulverized withdiethyl ether to obtain benzhydryl7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-triphenylphosphoranylidenemethyl-3-cephem-4-carboxylate(syn isomer) (3.7 g).

I.R. (Nujol): 3300-3170, 1730, 1670, 1580, 1540 cm⁻¹.

PREPARATION 8

To a suspension of L-serine (50 g) in water (500 ml) and dioxane (500ml) were added triethylamine (140 ml) and2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile (138 g), and themixture was stirred at ambient temperature for 24 hours. After removalof the dioxane, the remained aqueous solution was adjusted to pH 8.0with an aqueous sodium bicarbonate, and then washed four times withethyl acetate (200 ml). The aqueous solution was adjusted to pH 2.0 withconc. hydrochloric acid and then extracted twice with ethyl acetate (300ml). The combined ethyl acetate solution was washed with an aqueoussodium chloride, dried over anhydrous magnesium sulfate and thenconcentrated under reduced pressure. To the concentrate was addeddropwise a solution of diazodiphenylmethane in ethyl acetate till thestarting compound was disappeared on thin layer chromatography. Removalof the solvent gave a residue, which was pulverized with diisopropylether to obtain N-tert-butoxycarbonyl-L-serine benzhydryl ester (100 g).

I.R. (Nujol): 3250, 1746, 1677 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.37 (9H, s), 3.73 (2H, t, J=12.0 Hz), 4.20 (1H,m), 4.93 (1H, t, J=12 Hz), 6.82 (1H, s), 7.40 (10H, broad s).

PREPARATION 9

A mixture of DL-homoserine (50 g), triethylamine (140 ml),2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile (103.3 g), water (500ml) and dioxane (500 ml) was stirred at ambient temperature for 24hours. After removal of the dioxane, the remained aqueous solution wasadjusted to pH 8.5-9.0 with 10% aqueous sodium hydroxide and then washedwith ethyl acetate (500 ml×5). The resultant aqueous solution wasadjusted to pH 2.0 with conc. hydrochloric acid and then extracted withethyl acetate, followed by washing with an aqueous sodium chloride anddrying over anhydrous magnesium sulfate. To this solution was addeddropwise a solution of diazodiphenylmethane in ethyl acetate till thestarting compound was disappeared on thin layer chromatography. Removalof the solvent gave a residue, which was pulverized with diisopropylether to obtain N-tert-butoxycarbonyl-DL-homoserine benzhydryl ester(117.0 g), mp 125°-129° C.

IR (Nujol): 3500, 3320, 1735, 1687 cm⁻¹.

NMR δppm (CDCl₃): 1.43 (9H, s), 1.8-2.5 (2H, m), 3.6 (2H, m), 4.58 (1H,m), 5.5 (1H, d, J=8 Hz), 6.92 (1H, s), 7.3 (10H, s).

PREPARATION 10

A solution of 7-(2-phenylacetamido)-3-vinyl-3-cephem-4-carboxylic acid(15.3 g), N-tert-butoxycarbonyl L-serine benzhydryl ester (15 g),triphenylphosphine (15.9 g) and diethyl diazenedicarboxylate (10.6 g) intetrahydrofuran (450 ml) was heated under reflux for 3 hours. Thereaction mixture was concentrated under reduced pressure to give aresidue, which was dissolved in ethyl acetate (30 l), and washed with anaqueous sodium bicarbonate and an aqueous sodium chloride, followed bydrying over anhydrous magnesium sulfate. Removal of the solvent gave aresidue, which was chromatographed on silica gel (400 ml) eluting withmethylene chloride, and fractions containing a desired compound werecollected. Removal of the solvent gave a residue, which was pulverizedwith diisopropyl ether to obtainL-2-benzhydryloxycarbonyl-2-tert-butoxycarbonylaminoethyl7-(2-phenylacetamido)-3-vinyl-3-cephem-4-carboxylate (17.2 g).

IR (Nujol): 3350, 1767, 1735, 1718, 1678, 1653 cm⁻¹.

NMR δppm (DMSO-d₆): 1.40 (9H, s), 3.53, 4.00 (2H, Abq, J=18 Hz), 3.57(2H, s), 4.55 (3H, m), 5.13 (1H, d, J=5 Hz), 5.35 (1H, d, J=11 Hz), 5.61(1H, dd, J=5 Hz, 8 Hz), 5.68 (1H, d, J=18 Hz), 6.86 (1H, s), 6.92 (1H,dd, J=11 Hz, 18 Hz), 7.37 (5H, s), 7.57 (10H, broad s), 9.20 (1H, d, J=8Hz).

PREPARATION 11

A mixture of phosphorus pentachloride (4.5 g), pyridine (1.8 ml) andmethylene chloride (50 ml) was stirred at ambient temperature for halfan hour. To the resultant suspension was addedL-2-benzhydryloxycarbonyl-2-tert-butoxycarbonylaminoethyl7-(2-phenylacetamido)-3-vinyl-3-cephem-4-carboxylate (10 g) at 5° C.,and the mixture was stirred at the same temperature for half an hour.After the reaction mixture was poured into methanol (60 ml) at -30° C.,the mixture was stirred at -20° C. for half an hour, followed byaddition of water (50 ml), and then adjusting to pH 6.0 with 5% aqueoussodium hydroxide. After evaporation, the residue was extracted withmethylene chloride. The extract was washed with an aqueous sodiumchloride and then dried over anhydrous magnesium sulfate, followed bytreating with an activated charcoal. The filtrate was evaporated underreduced pressure, and thereto was added benzene, followed byazeotropically removing the pyridine by evaporation. The residue waspulverized with a mixed solvent of petroleum ether and diisopropyl etherto obtain L-2-benzhydryloxycarbonyl-2-tert-butoxycarbonylaminoethyl7-amino-3-vinyl-3-cephem-4-carboxylate (7.5 g).

IR (Nujol): 3350, 1773, 1737, 1709, 1693 cm⁻¹.

NMR δppm (DMSO-d₆): 1.37 (9H, s), 3.47, 3.93 (2H, ABq, J=18 Hz), 4.52(3H, m), 4.68, 5.02 (2H, ABq, J=5 Hz), 5.30 (1H, d, J=11 Hz), 5.58 (1H,d, J=18 Hz), 6.80 (1H, s), 6.82 (1H, dd, J=11 Hz, 18 Hz), 7.37 (10H, s).

PREPARATION 12

A suspension of (2-formamidothiazol-5-yl)glyoxylic acid (2.4 g) andmethoxylamine hydrochloride (5.0 g) in water (144 ml) was adjusted to pH4.9-5.0 with a saturated aqueous sodium bicarbonate and the mixture wasstirred at ambient temperature for 4.7 hours. After water was addedthereto in order to dissolve the insoluble material therein, the aqueoussolution was concentrated to a volume of 100 ml. The precipitatedmaterial was collected by filtration, washed with water, followed bydissolving in a mixture of tetrahydrofuran and water. This solution waspoured into a mixture of ethyl acetate and water, and the organic layerwas separated out. After the aqueous solution was extracted with ethylacetate, the combined ethyl acetate solution was washed with an aqueoussodium chloride and then dried over anhydrous magnesium sulfate. Removalof the solvent gave 2-(2-formamidothiazol-5-yl)-2-methoxyiminoaceticacid (anti isomer) (0.9 g), mp 159° C. (dec.). The filtrate obtainedabove was further concentrated to a volume of 70 ml, and theprecipitated material was collected by filtration to recover the sameproduct (0.23 g). Total yield: 1.13 g.

IR (Nujol): 3180, 1700, 1560, 1460 cm⁻¹.

NMR δppm (DMSO-d₆): 4.14 (3H, s), 8.30 (1H, s), 8.57 (1H, s).

Further, to the filtrate was added ethyl acetate, and the mixture wasadjusted to pH 1.5 with 10% hydrochloric acid, followed by separatingout the ethyl acetate layer. After the remained aqueous solution wasextracted with ethyl acetate, the combined ethyl acetate solution waswashed with an aqueous sodium chloride and then dried over anhydrousmagnesium sulfate. Removal of the solvent gave2-(2-formamidothiazol-5-yl)-2-methoxyiminoacetic acid (syn isomer) (0.87g), mp 183° C. (dec.).

IR (Nujol): 1720, 1650, 1535, 1465 cm⁻¹.

NMR δppm (DMSO-d₆): 3.92 (3H, s), 7.58 (1H, s), 8.57 (1H, s).

PREPARATION 13

To a solution of bromoacetyl bromide (20 g) in tetrahydrofuran (200 ml)were added N-tert-butoxycarbonyl-L-serine benzhydryl ester (10.84 g) andN,N-dimethylaniline (6.8 ml), and the mixture was stirred at 20° to 23°C. for 80 minutes. After adjusting to pH 5.0 with 10% aqueous sodiumhydroxide and 5% aqueous sodium bicarbonate, the tetrahydrofuran wasremoved by evaporation. The residue was dissolved in a mixture of ethylacetate (200 ml) and water (100 ml), and then washed with 5%hydrochloric acid and an aqueous sodium chloride, followed by dryingover anhydrous magnesium sulfate. Removal of the solvent gave a residue,which was pulverized with diisopropyl ether to obtainL-2-benzhydryloxycarbonyl-2-tert-butoxycarbonylaminoethyl 2-bromoacetate(21.3 g), mp 92°-94° C.

IR (Nujol): 3350, 1735, 1727, 1704, 1160 cm⁻¹.

NMR δppm (DMSO-d₆): 1.40 (9H, s), 4.03 (2H, s), 4.67 (3H, m), 6.85 (1H,s), 7.37 (10H, s).

PREPARATION 14

A mixture of L-2-benzhydryloxycarbonyl-2-tert-butoxycarbonylaminoethyl2-bromoacetate (20 g), N-hydroxyphthalimide (6.7 g), triethylamine (8.5ml) and N,N-dimethylformamide (80 ml) was stirred at 10° to 15° C. forhalf an hour. The reaction mixture was poured into 5% aqueous sodiumchloride (1.5 l), and the precipitated material was collected byfiltration and then washed with water, followed by dissolving in ethylacetate (300 ml). The solution was washed twice with an aqueous sodiumchloride and dried over anhydrous magnesium sulfate, followed byevaporation to give a residue, which was pulverized with diisopropylether to obtainL-2-benzhydryloxycarbonyl-2-tert-butoxycarbonylaminoethyl2-phthalimidooxyacetate (24.5 g), mp 45°-50° C.

IR (Nujol): 3420, 1740, 1720 (shoulder) cm⁻¹.

NMR δppm (DMSO-d₆): 1.38 (9H, s), 4.55 (3H, broad s), 4.89 (2H, broads), 6.93 (1H, s), 7.47 (10H, broad s), 8.00 (4H, s).

PREPARATION 15

To a solution of N-hydroxyphthalimide (4.3 g),N-tert-butoxycarboyl-DL-homoserine benzhydryl ester (10 g) andtriphenylphosphine in tetrahydrofuran (100 ml) was added dropwise adiethyl diazenedicarboxylate (4.6 g) at ambient temperature withstirring, and the stirring was continued at 32° to 35° C. for 3 hours.Removal of the solvent gave a residue, which was chromatographed onsilica gel eluting with a mixed solvent of benzene and acetone.Fractions containing a desired compound were collected and thenevaporated to obtain benzhydrylDL-2-tert-butoxycarbonylamino-4-phthalimidooxybutyrate (10 g), mp162°-163° C.

IR (Nujol): 3360, 1740, 1722, 1681 cm⁻¹.

NMR δppm (CDCl₃): 1.45 (9H, s), 2.37 (2H, q, J=6 Hz), 4.26 (2H, t, J=6Hz), 4.58 (1H, m), 5.73 (1H, d, J=8 Hz), 6.90 (1H, s), 7.3 (10H, s),7.77 (4H, s).

PREPARATION 16

To a solution ofL-2-benzhydryloxycarbonyl-2-tert-butoxycarbonylaminoethyl2-phthalimidooxyacetate (20 g) in methylene chloride (100 ml) was addeda solution of hydrazine monohydrate (3.5 g) in methanol underice-cooling, and the mixture was stirred below 15° C. for an hour. Theprecipitated material was collected by filtration and washed withmethylene chloride. The washings and the above obtained methylenechloride solution were combined, adjusted to pH 7.0 with 5% hydrochloricacid, and washed with an aqueous sodium chloride, followed by dryingover anhydrous magnesium sulfate. Removal of the solvent gave a residue,which was chromatographed on silica gel (200 ml) eluting with a mixedsolvent of benzene and ethyl acetate, and fractions containing a desiredcompound were collected. Removal of the solvent gave a residue, whichwas pulverized with diisopropyl ether to obtainL-2-benzhydryloxycarbonyl-2-tert-butoxycarbonylaminoethyl2-aminooxyacetate (10.5 g), mp 90°-92° C.

IR (Nujol): 3400, 1745, 1720 cm⁻¹.

NMR δppm (DMSO-d₆): 1.38 (9H, s), 4.10 (2H, s), 4.45 (3H, broad s), 6.30(2H, s), 6.84 (1H, s), 7.37 (10H, s).

PREPARATION 17

A solution of benzhydrylDL-2-tert-butoxycarbonylamino-4-phthalimidooxybutyrate (7.0 g) inmethylene chloride (100 ml) was added dropwise to a solution ofhydrazine monohydrate (2.0 g) in methanol (6 ml) at ambient temperature,and the mixture was stirred for half an hour. The precipitated materialwas collected by filtration and then washed with methylene chloride (30ml). After the filtrate and washings were combined, thereto was addedwater, followed by adjusting to pH 7.0 with conc.hydrochloric acid. Theseparated methylene chloride solution was washed with water and anaqueous sodium chloride, followed by drying over anhydrous magnesiumsulfate. Removal of the solvent gave a residue which was pulverized withdiisopropyl ether to obtain benzhydrylDL-2-tert-butoxycarbonylamino-4-aminooxybutyrate (5.0 g), mp 92°-93° C.

IR (Nujol): 3340, 3305, 1730, 1695 cm⁻¹.

NMR δppm (DMSO-d₆): 1.38 (9H, s), 1.95 (2H, m), 3.58 (2H, t, J=6 Hz),4.18 (1H, m), 5.92 (2H, s), 6.82 (1H, s), 7.37 (10H, s).

PREPARATION 18

To a suspension of (2-formamidothiazol-4-yl)-glyoxylic acid (3.6 g) inpyridine (3.7 ml) and water (33 ml) was added a solution ofL-2-benzhydryloxycarbonyl-2-tert-butoxycarbonylaminoethyl2-aminooxyacetate (10.5 g) in tetrahydrofuran (30 ml), and the mixturewas stirred at ambient temperature for 5 hours. Water was added to thereaction mixture, followed by adjusting to pH 1.6 with conc.hydrochloric acid. After extraction with ethyl acetate, the extract waswashed with an aqueous sodium chloride, and then dried over anhydrousmagnesium sulfate. Removal of the solvent gave a residue, which waspulverized with diisopropyl ether to obtain2-(2-formamidothiazol-4-yl)-2-(L-2-benzhydryloxycarbonyl-2-tert-butoxycarbonylaminoethoxycarbonylmethoxyimino)aceticacid (syn isomer) (11.7 g), mp 110°-113° C.

IR (Nujol): 3330, 3180, 1756 (shoulder), 1743, 1715, 1703 cm⁻¹.

NMR δppm (DMSO-d₆): 1.38 (9H, s), 4.47 (3H, broad s), 4.70 (2H, broads), 6.85 (1H, s), 7.40 (10H, broad s), 7.55 (1H, s), 8.55 (1H, s), 12.70(1H, broad s).

PREPARATION 19

To a suspension of 2-(2-formamidothiazol-4-yl)-glyoxylic acid (3.40 g)in pyridine (3.6 ml) and water (32 ml) was added a solution ofbenzhydryl DL-2-tert-butoxycarbonylamino-4-aminooxybutyrate (7.0 g) intetrahydrofuran (30 ml) at ambient temperature, and the mixture wasstirred for 3 hours. The reaction mixture was poured into ethyl acetate(200 ml), and the separated ethyl acetate layer was washed with dilutehydrochloric acid and an aqueous sodium chloride, followed by dryingover anhydrous magnesium sulfate. Removal of the solvent gave2-(2-formamidothiazol-4-yl)-2-(DL-3-benzhydryloxycarbonyl-3-tert-butoxycarbonylaminopropoxyimino)aceticacid (syn isomer) (9.0 g), mp 61°-65° C.

IR (Nujol): 3150, 1740, 1695 cm⁻¹.

NMR δppm (DMSO-d₆): 1.4 (9H, s), 2.1 (2H, m), 4.2 (3H, m), 6.82 (1H, s),7.33 (10H, s), 7.53 (1H, s), 8.53 (1H, s).

PREPARATION 20

Vilsmeir reagent, which was prepared from N,N-dimethylformamide (0.48 g)and phosphorus oxychloride (1.0 g), was suspended in ethyl acetate (20ml), and thereto was added 4-bromo-2-methoxyiminoacetoacetic acid (synisomer) (1.34 g) under ice-cooling, followed by stirring at the sametemperature for half an hour to prepare the activated acid solution.This solution was added to a solution of benzhydryl7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (2.15 g) andtrimethylsilylacetamide (3.93 g) in ethyl acetate (30 ml) at -20° C.,and the mixture was stirred at -20° to 0° C. for 1.5 hours. To thereaction mixture were added ethyl acetate (100 ml) and water (100 ml),and the separated ethyl acetate solution was washed with a saturatedaqueous sodium bicarbonate and an aqueous sodium chloride, followed bydrying over anhydrous magnesium sulfate. Removal of the solvent gave aresidue, which was washed with diethyl ether to obtain benzhydryl7-(4-bromo-2-methoxyiminoacetoacetamido)-3-vinyl-3-cephem-4 -carboxylate(syn isomer) (2.5 g).

IR (Nujol): 3280, 1770, 1710, 1700, 1660, 1600, 1560 cm⁻¹.

NMR δppm (DMSO-d₆): 3.78 (2H, q, J=18 Hz), 4.07 (3H, s), 4.63 (2H, s),5.27 (1H, d, J=5 Hz), 5.30 (1H, d, J=11 Hz), 5.63 (1H, d, J=17 Hz), 5.93(1H, dd, J=5 Hz, 8 Hz), 6.78 (1H, dd, J=11 Hz, 17 Hz), 6.98 (1H, s),7.17-7.67 (10H, m), 9.57 (1H, d, J=8 Hz).

PREPARATION 21

To a solution of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylatehydrochloride (6.4 g) and trimethylsilylacetamide (9.8 g) in ethylacetate (80 ml) was added 4-bromo-3,3-diethoxy-2-methoxyiminobutyrylchloride (syn isomer) (5.0 g) at -20° C. with stirring, and the stirringwas continued at -20° to -5° C. for an hour. To the reaction mixturewere added ethyl acetate and water, and the separated ethyl acetatesolution was washed with a saturated aqueous sodium bicarbonate and anaqueous sodium chloride, followed by drying over anhydrous magnesiumsulfate. Removal of the solvent gave benzhydryl7-(4-bromo-3,3-diethoxy-2-methoxyiminobutyramido)-3-vinyl-3-cephem-4-carboxylate(syn isomer) (10.1 g).

IR (Nujol): 1780, 1720, 1610, 1510 cm⁻¹.

NMR δppm (DMSO-d₆): 1.13 (3H, t, J=7 Hz), 3.60 (2H, q, J=7 Hz), 3.76(2H, m), 3.83 (3H, s), 5.22 (1H, d, J=5 Hz), 5.24 (1H, d, J=11 Hz), 5.60(1H, d, J=17 Hz), 5.82 (1H, dd, J=5 Hz, 8 Hz), 6.70 (1H, dd, J=11 Hz, 17Hz), 6.93 (1H, s), 7.17-7.60 (10H, m), 9.00 (1H, d, J=8 Hz)

PREPARATION 22

To a solution of benzhydryl7-(4-bromo-3,3-diethoxy-2-methoxyiminobutyramido)-3-vinyl-3-cephem-4-carboxylate(syn isomer) (6.5 g) in methylene chloride (60 ml) was added conc.hydrochloric acid (6 ml) at 3° to 5° C., and the mixture was stirredfrom under ice-cooling to at ambient temperature for 8 hours. Aftermethylene chloride (100 ml) was added to the reaction mixture, it waswashed with water and then dried over anhydrous magnesium sulfate.Removal of the solvent gave a residue, which was washed with diethylether to obtain benzhydryl7-(4-bromo-2-methoxyiminoacetoacetamido)-3-vinyl-3-cephem-4-carboxylate(syn isomer) (3.5 g).

IR (Nujol): 3280, 1770, 1710, 1700, 1660, 1600, 1560 cm⁻¹.

NMR δppm (DMSO-d₆): 3.78 (2H, q, J=18 Hz), 4.07 (3H, s), 4.63 (2H, s),5.27 (1H, d, J=5 Hz), 5.30 (1H, d, J=11 Hz), 5.63 (1H, d, J=17 Hz), 5.93(1H, dd, J=5 Hz, 8 Hz), 6.78 (1H, dd, J=11 Hz, 17 Hz), 6.98 (1H, s),7.17-7.67 (10H, m), 9.57 (1H, d, J=8 Hz)

PREPARATION 23

To a solution of benzhydryl7-(4-bromo-3,3-diethoxy-2-methoxyiminobutyramido)-3-vinyl-3-cephem-4-carboxylate(syn isomer) (3.36 g) and anisole (2.1 g) in methylene chloride (20 ml)was added trifluoroacetic acid (8.0 g) under ice-cooling with stirring,and the stirring was continued at ambient temperature for an hour. Afterremoval of the solvent, the residue was dissolved in a mixture of ethylacetate and water. To the separated ethyl acetate solution was addedwater, followed by adjusting to pH 7 with a saturated aqueous sodiumbicarbonate. To the separated aqueous solution was added ethyl acetate,followed by adjusting to pH 2 with 10% hydrochloric acid. The ethylacetate layer was separated out, washed with an aqueous sodium chlorideand then dried over anhydrous magnesium sulfate. Removal of the solventgave7-(4-bromo-2-methoxyiminoacetoacetamido)-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (1.6 g).

IR (Nujol): 3300-3200, 1780, 1700, 1675 (shoulder), 1540 cm⁻¹.

PREPARATION 24

To a suspension of hydroxylamine hydrochloride (22.3 g) in ethanol (25ml) was added a phenolphthalein indicator (0.3 ml), and thereto wasadded dropwise a solution of potassium hydroxide (23.1 g) in ethanol(185 ml) little by little until dark red color of the mixture changedinto pale red, followed by stirring for an hour. After removal of thepotassium chloride by filtration, to the filtrate was added ethyl2-cyano-2-methoxyiminoacetate (50 g), followed by stirring at 20° to 30°C. for 3 days. Removal of the solvent gave ethyl3-amino-3-hydroxyimino-2-methoxyiminopropionate, which was dissolved indioxane (200 ml) and then evaporated. The residue was dissolved indioxane (130 ml), and thereto were added pyridine (75.8 g) and thentrichloroacetyl chloride (87.3 g) under ice-cooling below 10° C.,followed by stirring at the same temperature for an hour and allowing tostand overnight. After removal of the insoluble materials by filtration,the filtrate was evaporated to dryness. To the residue were addeddiethyl ether and water, and the separated organic solution was washedwith dilute hydrochloric acid and an aqueous solution of sodiumchloride, followed by drying over anhydrous magnesium sulfate. Removalof the solvent gave an oil, which was chromatographed on silica geleluting with a mixed solvent of benzene and n-hexane ( 3:1 by volume),and fractions containing a desired compound were collected. Removal ofthe solvent gave ethyl2-(5-trichloromethyl-1,2,4-oxadiazol-3-yl)-2-methoxyiminoacetate (antiisomer) (22.6 g).

IR (Film): 1730, 1600, 1565 cm⁻¹.

NMR δppm (CDCl₃): 1.37 (3H, t, J=7 Hz), 4.22 (3H, s), 4.42 (2H, q, J=7Hz).

PREPARATION 25

To a solution of ethyl2-(5-trichloromethyl-1,2,4-oxadiazol-3-yl)-2-methoxyiminoacetate (antiisomer) (9 g) in dioxane (90 ml) was added conc. hydrochloric acid (3.5ml), and the mixture was heated under reflux for 50 minutes. Afterremoval of the solvent, the residue was dissolved in ethyl acetate,washed with an aqueous sodium chloride, and then dried over anhydrousmagnesium sulfate. Removal of the solvent gave a residue, which waschromatographed on silica gel eluting with a mixed solvent of benzeneand n-hexane (1:1 by volume). Fractions containing a desired compoundwere collected and evaporated to obtain ethyl2-(5-trichloromethyl-1,2,4-oxadiazol-3-yl)-2-methoxyiminoacetate (synisomer) (3.7 g). The starting compound (1.7 g) was recovered from thesubsequent fractions.

IR (Film): 1740, 1600, 1570, 1495 cm⁻¹.

NMR δppm (CDCl₃): 1.38 (3H, t, J=7 Hz), 4.17 (3H, s), 4.45 (2H, q, J=7Hz).

PREPARATION 26

To ethyl2-(5-trichloromethyl-1,2,4-oxadiazol-3-yl)-2-methoxyiminoacetate (synisomer) (3.4 g) was added liquid ammonia (17 ml). After givinghomogenous solution, it was poured into a petri dish, followed byremoving liquid ammonia by ventilation. To the residue were added waterand ethyl acetate, and the separated ethyl acetate solution was washedwith an aqueous sodium chloride and dried over anhydrous magnesiumsulfate. Removal of the solvent gave a residue, which was washed withdiisopropyl ether to obtain ethyl2-(5-amino-1,2,4-oxadiazol-3-yl)-2-methoxyiminoacetate (syn isomer)(1.75 g), mp 143°-146° C.

IR (Nujol): 3440, 3310, 3240, 3180, 1720, 1660, 1600, 1505 cm⁻¹.

NMR δppm (DMSO-d₆): 1.25 (3H, t, J=7 Hz), 4.00 (3H, s), 4.32 (2H, q, J=7Hz), 8.17 (2H, s).

PREPARATION 27

Ethyl 2-(5-amino-1,2,4-oxadiazol-3-yl)-2-methoxyiminoacetate (synisomer) (2.5 g) was added to 1N aqueous sodium hydroxide (14 ml), andthe solution was stirred at ambient temperature for an hour. Thereaction mixture was adjusted to pH 1.8 with 10% hydrochloric acid,salted out with sodium chloride, and then extracted with a mixture ofethyl acetate and tetrahydrofuran. After drying over anhydrous magnesiumsulfate, the extract was evaporated to dryness to give a residue, whichwas washed with diisopropyl ether to obtain2-(5-amino-1,2,4-oxadiazol-3-yl)-2-methoxyiminoacetic acid (syn isomer)(2.0 g).

IR (Nujol): 3420, 3330, 3250, 3180, 1720, 1665, 1600, 1500 cm⁻¹.

NMR δppm (DMSO-d₆): 4.00 (3H, s), 8.15 (2H, s).

PREPARATION 28

N-(2-Pyridylmethoxy)phthalimide (50 g) was suspended in ethanol (500ml), and thereto was added hydrazine monohydrate (20.8 g) at 60° C.,followed by stirring at the same temperature for an hour. To thereaction mixture was added conc. hydrochloric acid (60 ml) dissolved inwater (450 ml) under cooling, and the precipitated materials wereremoved by filtration. The ethanol was removed by evaporation from thefiltrate, and the precipitated materials therein were further removed byfiltration. To the filtrate was added ethanol (500 ml) and then adjustedto pH 7.0 with 4N aqueous sodium hydroxide. Thereto was added(2-formamidothiazol-4-yl)glyoxylic acid (30.3 g), followed by adjustingto pH 4.5 with 10% hydrochloric acid and stirring for 1.5 hours. Duringthe stirring, the pH value of the mixture was kept at 4 to 4.5 with 4Naqueous sodium hydroxide. After the reaction mixture was adjusted to pH7.5 with 4N aqueous sodium hydroxide, the ethanol was removed byevaporation. The resultant aqueous solution was adjusted to pH 3.0 with10% hydrochloric acid, and the precipitated crystals were collected byfiltration to obtain2-(2-formamidothiazol-4-yl)-2-(2-pyridylmethoxyimino)acetic acid (synisomer) (35.4 g).

IR (Nujol): 3100, 1680, 1610, 1560, 1540 cm⁻¹.

NMR δppm (NaHCO₃ +D₂ O): 5.3 (2H, s), 7.47 (1H, s), 7.17-8.07 (3H, m),8.47 (1H, s), 8.33-8.67 (1H, m)

PREPARATION 29

2-(2-Formamidothiazol-4-yl)-2-(3-pyridylmethoxyimino)-acetic acid (synisomer) (8.0 g) was obtained by reacting(2-formamidothiazol-4-yl)glyoxylic acid (8.8 g) with3-pyridylmethoxyamine, which was prepared fromN-(3-pyridylmethoxy)phthalimide (14.5 g) and hydrazine monohydrate (6.3g), according to a similar manner to that of Preparation 28.

IR (Nujol): 3400, 3050, 1670, 1550 cm⁻¹.

NMR δppm (NaHCO₃ +D₂ O): 5.28 (2H, s), 7.44 (1H, s), 7.24-7.50 (1H, m),7.82 (1H, m), 8.46 (1H, s), 8.14-8.66 (2H, m).

PREPARATION 30

2-(2-Formamidothiazol-4-yl)-2-(4-pyridylmethoxyimino)acetic acid (synisomer) (10.5 g) was obtained by reacting(2-formamidothiazol-4-yl)glyoxylic acid (10.3 g) with4-pyridylmethoxyamine, which was prepared fromN-(4-pyridylmethoxy)phthalimide (17.0 g) and hydrazine monohydrate (6.0g), according to a similar manner to that of Preparation 28.

IR (Nujol): 3500, 1650, 1560, 1500 cm⁻¹.

NMR δppm (NaHCO₃ +D₂ O): 5.22 (2H, s), 7.38 (1H, s), 7.27-7.47 (2H, m),8.42 (1H, s), 8.33-8.55 (2H, m).

PREPARATION 31

To a solution of sodium7-(5-amino-5-carboxypentanamido)-3-hydroxymethyl-3-cephem-4-carboxylate(118.6 g) in water (1000 ml) and acetone (600 ml) was added dropwisebenzoyl chloride (42.1 g) under ice-cooling with stirring at 10° C.while the reaction mixture was continually adjusted to pH 6.5 to 7.5with 20% aqueous sodium carbonate. After the stirring was continued atthe same temperature for an hour, the reaction mixture was adjusted topH 6.0 with conc. hydrochloric acid, followed by removing the acetoneand washing with ethyl acetate (500 ml). To this aqueous solution wasadded ethyl acetate (300 ml), and thereto was added a solution ofdiphenyldiazomethane in ethyl acetate till the starting compound wasdiappeared on a thin layer chromatography, followed by adjusting to pH3.0 with conc. hydrochloric acid. The ethyl acetate layer was separated,washed with an aqueous sodium chloride and then dried over magnesiumsulfate, followed by evaporation under reduced pressure. After theresidue was dissolved in acetone (400 ml), the solution was addeddropwise to diisopropyl ether (4000 ml). The precipitated crystals werecollected by filtration and then dried to obtain benzhydryl7-(5-benzamido-5-benzhydryloxycarbonylpentanamido)-3-hydroxymethyl-3-cephem-4-carboxylate(224.8 g), mp 100°-110° C.

IR (Nujol): 3270, 1770, 1730, 1660, 1640 cm⁻¹.

NMR δppm (DMSO-d₆): 1.3-2.7 (6H, m), 3.38 (1H, s), 3.63 (2H, m), 4.27(2H, d, J=5 Hz), 4.67 (1H, m), 5.15 (1H, d, J=5 Hz), 5.77 (1H, dd, J=5Hz, 8 Hz), 6.87 (1H, s), 6.95 (1H, s), 7.43 (25H, m), 7.97 (1H, m), 8.87(1H, m).

PREPARATION 32

To a solution of benzhydryl7-(5-benzamido-5-benzhydryloxycarbonylpentanamido)-3-hydroxymethyl-3-cephem-4-carboxylate(100 g) in methylene chloride (600 ml) was added at a time phosphoruspentachloride (25.6 g) at -30° C., followed by adding dropwise pyridine(9.8 g) at the same temperature. After the reaction mixture was stirredat -20° C. for an hour, it was poured into a mixture of methylenechloride (500 ml) and water (300 ml). The separated organic layer waswashed with an aqueous sodium chloride, dried over magnesium sulfate andthen evaporated to dryness to obtain benzhydryl7-(5-benzamido-5-benzhydryloxycarbonylpentanamido)-3-chloromethyl-3-cephem-4-carboxylate(114.5 g), mp 90°-110° C. (dec.).

IR (Nujol): 1780, 1725, 1640 cm⁻¹.

NMR δppm (DMSO-d₆): 1.3-2.5 (6H, m), 3.67 (2H, m), 4.43 (2H, m), 4.67(1H, m), 5.22 (1H, d, J=5 Hz), 5.83 (1H, m), 6.83 (1H, s), 7.00 (1H, s),7.4 (25H, m), 7.92 (1H, m), 8.90 (1H, m).

PREPARATION 33

To a solution of benzhydryl7-(5-benzamido-5-benzhydryloxycarbonylpentanamido)-3-chloromethyl-3-cephem-4-carboxylate(102 g) in N,N-dimethylformamide (150 ml) were added triphenylphosphine(48.5 g) and sodium iodide (18.4 g), and the mixture was stirred atambient temperature for 1.5 hours. The reaction mixture was addeddropwise to isopropyl alcohol (5000 ml), and the precipitated materialwas collected by filtration and washed with diisopropyl ether to obtain[7-(5-benzamido-5-benzhydryloxycarbonylpentanamido)-4-benzhydryloxycarbonyl-3-cephem-3-yl]methyl-triphenylphosphoniumiodide (123.5 g), mp 165°-175° C. (dec.).

IR (Nujol): 1780, 1730, 1710, 1650 cm⁻¹.

NMR δppm (DMSO-d₆): 1.3-2.6 (6H, m), 4.33 (2H, m), 4.67 (2H, m), 5.13(1H, m), 5.33 (1H, d, J=5 Hz), 5.75 (1H, m), 6.33 (1H, s), 6.83 (1H, s),7.0-8.3 (41H, m), 8.92 (1H, m).

PREPARATION 34

To a solution of[7-(5-benzamido-5-benzhydryloxycarbonylpentanamido)-4-benzhydryloxycarbonyl-3-cephem-3-yl]methyl-triphenyl-phosphoniumiodide (123.5 g) in methylene chloride (1000 ml) was added 36% aqueousformaldehyde (300 ml), followed by adjusting to pH 9.0 with 20% aqueoussodium bicarbonate. After the mixture was stirred at 25° C. for 2 hours,it was adjusted to pH 5.0 with conc. hydrochloric acid. The separatedorganic solution was concentrated, and to the concentrate was addedethyl acetate. The precipitated crystals were collected by filtrationand then dried to obtain benzhydryl7-(5-benzamido-5-benzhydryloxycarbonylpentanamido)-3-vinyl-3-cephem-4-carboxylate(63.5 g), mp 180°-184° C. (dec.).

IR (Nujol): 3300, 1770, 1730, 1710, 1650 cm⁻¹.

NMR δppm (DMSO-d₆): 1.3-2.6 (6H, m), 3.72 (2H, m), 4.67 (1H, m), 5.1-5.6(2H, m), 5.7-5.9 (2H, m), 6.83 (1H, dd, J=12 Hz, 18 Hz), 6.86 (1H, s),7.0 (1H, s), 7.42 (25H, m), 7.98 (1H, m), 8.92 (1H, m).

PREPARATION 35

To a suspension of phosphorus pentachloride (15.5 g) in methylenechloride (200 ml) was added dropwise pyridine (5.9 g) at 5° to 10° C.with stirring, and the stirring was continued at 5° C. for 20 minutes.Thereto was added at a time benzhydryl7-(5-benzamido-5-benzhydryloxycarbonylpentanamido)-3-vinyl-3-cephem-4-carboxylate(20 g) at 5° C., and the mixture was stirred at the same temperature for2 hours. To the reaction mixture was added gradually methanol (120 ml)at -40° C., followed by stirring at -20° to -10° C. for an hour. Removalof the solvent gave a residue, to which ethyl acetate (300 ml) and water(50 ml) were added. The mixture was stirred under ice-cooling for awhile, and the precipitated crystals were collected by filtration andthen washed with isopropyl alcohol to obtain benzhydryl7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (8.4 g), mp180°-195° C. (dec.).

IR (Nujol): 1760, 1705, 1580 cm⁻¹.

NMR δppm (DMSO-d₆): 3.88 (2H, q, J=18 Hz), 5.1-5.4 (2H, m), 5.58 (1H, d,J=6 Hz), 5.93 (1H, m), 6.97 (1H, s), 7.0, (1H, dd, J=12 Hz, 18 Hz), 7.42(10H, m), 9.17 (2H, m).

PREPARATION 36

To a suspension of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylatehydrochloride (48 g) in methanol (250 ml) and anisole (70 ml) was addedp-toluenesulfonic acid (85 g), and the mixture was stirred at 50° C. for2 hours. The reaction mixture was poured into 10% aqueous sodiumcarbonate (600 ml) and ethyl acetate (700 ml), followed by adjusting topH 7.5 with 20% aqueous sodium carbonate. The separated aqueous solutionwas washed with ethyl acetate (500 ml) and then adjusted to pH 2.5 withconc. hydrochloric acid, followed by stirring under ice-cooling for anhour. The precipitated crystals were collected by filtration and washedwith acetone to obtain 7-amino-3-vinyl-3-cephem-4-carboxylic acid (15.4g), mp 200° to 230° C. (dec.).

IR (Nujol): 1800, 1605 cm⁻¹.

NMR δppm (D₂ O+NaHCO₃): 3.67 (2H, s), 4.8-5.8 (5H, m), 6.88 (1H, dd,J=12 Hz, 18 Hz).

PREPARATION 37

To a suspension of phosphorus pentachloride (27.0 g) in methylenechloride (200 ml) was added dropwise pyridine (10.3 g) at 0° C.,followed by stirring at 5° C. for 20 minutes. Thereto was added at atime benzhydryl7-(5-benzamido-5-benzhydryloxycarbonylpentanamido)-3-hydroxymethyl-3-cephem-4-carboxylate(21.0 g) at -40° C., followed by stirring at -30° C. for an hour and at-10° C. for additional an hour. To the reaction mixture was added at atime at -40° C. methanol (100 ml), which was pre-cooled to -40° C.,followed by stirring at -10° C. for an hour. Removal of the solvent gavea residue, to which methylene chloride (100 ml), water (30 ml) anddiisopropyl ether (100 ml) were added in turn, and the mixture wasstirred under ice-cooling for a while. The precipitated crystals werecollected by filtration and suspended in ethyl acetate (300 ml),followed by adjusting to pH 8.0 with an aqueous sodium bicarbonate. Theseparated organic solution was washed with an aqueous sodium chlorideand then dried over magnesium sulfate. Removal of the solvent gavebenzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate (2.8 g), mp135°-140° C. (dec.).

IR (Nujol): 3400, 1760, 1725, 1650 cm⁻¹.

NMR δppm (DMSO-d₆): 3.60 (2H, q, J=17 Hz), 4.38 (2H, s), 4.85 (1H, d,J=5 Hz), 5.05 (1H, d, J=5 Hz), 6.95 (1H, s), 7.4 (10H, m), 8.8 (2H, m).

PREPARATION 38

To a solution of benzhydryl7-amino-3-chloromethyl-3-cephem-4-carboxylate (8.0 g) inN,N-dimethylformamide (40 ml) were added molecular sieve (10 g) andbenzaldehyde (2.1 g), followed by stirring at 40° C. for 40 minutes.Thereto were added sodium iodide (2.9 g) and triphenylphosphine (10.1g), followed by stirring at 40° C. for an hour. The reaction mixture wasadded dropwise to a mixture of diisopropyl ether (200 ml) and ethylacetate (100 ml), and the precipitated crystals were collected byfiltration and then dried to obtain[4-benzhydryloxycarbonyl-7-benzylideneamino-3-cephem-3-yl]methyl-triphenyl-phosphoniumiodide (16.9 g), mp 150°-158° C. (dec.).

IR (Nujol): 1780, 1705, 1635 cm⁻¹.

NMR δppm (DMSO-d₆): 3.67 (2H, m), 5.2 (2H, m), 5.58 (1H, d, J=5 Hz),5.82 (1H, d, J=5 Hz), 6.30 (1H, s), 7.2-8.3 (30H, m), 8.70 (1H, s).

PREPARATION 39

To a solution of[4-benzhydryloxycarbonyl-7-benzylidene-amino-3-cephem-3-yl]methyl-triphenylphosphoniumiodide (16.9 g) in methylene chloride (200 ml) and water (100 ml) wasadded 36% aqueous formaldehyde (48 ml), followed by adjusting to pH 9.0with sodium carbonate. After the mixture was stirred at ambienttemperature for an hour, the separated organic solution was washed withan aqueous sodium chloride and then dried over magnesium sulfate.Removal of the solvent gave benzhydryl7-benzylideneamino-3-vinyl-3-cephem-4-carboxylate (8.6 g), mp 124°-132°C.

IR (Nujol): 1770, 1710, 1630 cm⁻¹.

NMR δppm (DMSO-d₆): 3.75 (2H, q, J=18 Hz), 5.1-5.8 (4H, m), 6.75 (1H,dd, J=10 Hz, 18 Hz), 6.93 (1H, s), 7.1-8.0 (15H, m), 8.58 (1H, s).

PREPARATION 40

To a suspension of benzhydryl7-benzylideneamino-3-vinyl-3-cephem-4-carboxylate (8.6 g) in anisole (10ml) was added dropwise trifluoroacetic acid (10 ml) at -20° C., and thereaction temperature was gradually raised to ambient temperature withstirring, followed by stirring at ambient temperature for half an hour.The reaction mixture was poured into a mixture of ethyl acetate (100 ml)and a saturated aqueous sodium bicarbonate (100 ml), and then themixture was adjusted to pH 7.5 with 20% aqueous sodium carbonate. Theseparated aqueous solution was washed with ethyl acetate (100 ml) andadjusted to pH 7.2 with conc. hydrochloric acid, followed by subjectingto column chromatography on alumina (10 ml). Elution was carried outwith 15% aqueous sodium chloride, and fractions containing a desiredcompound were collected and then adjusted to pH 3.3 with conc.hydrochloric acid. The precipitated crystals were collected byfiltration, washed with acetone and dried to obtain7-amino-3-vinyl-3-cephem-4-carboxylic acid (2.0 g), mp 200°-230° C.(dec.).

IR (Nujol): 1800, 1605 cm⁻¹.

NMR δppm (D₂ O+NaHCO₃): 3.67 (2H, s), 4.8-5.8 (5H, m), 6.88 (1H, dd,J=12 Hz, 18 Hz).

PREPARATION 41

To a solution of N-hydroxyphthalimide (70.08 g) in acetonitrile (300 ml)were added triethylamine (48 g) and tert-butyl 4-bromocrotonate (96.0 g)with stirring, and the mixture was refluxed under heating for 1.5 hours.The reaction mixture was poured into water (600 ml), followed byextraction with ethyl acetate. The extract was washed with a saturatedaqueous sodium chloride, dried over magnesium sulfate and thenevaporated to dryness under reduced pressure to give a residue, whichwas pulverized with n-hexane. The resultant substance was subjected tocolumn chromatography on silica gel eluting with a mixed solvent ofn-hexane, ethyl acetate and diisopropyl ether (5:0.5:4.5 by volume), andthe fractions containing a desired compound were collected. Removal ofthe solvent gave a residue, which was pulverized with n-hexane andcollected by filtration to obtain tert-butyl 4-phthalimidooxycrotonate(41.7 g).

NMR δppm (DMSO-d₆): 1.45 (9H, s), 4.90 (2H, m), 6.09 (1H, m), 6.66-7.19(1H, m), 7.86 (4H, s).

PREPARATION 42

To a solution of tert-butyl 4-phthalimidooxycrotonate (20.0 g) inmethylene chloride (140 ml) was added a solution of hydrazinemonohydrate (5.0 g) in methanol (10 ml) with stirring, and the stirringwas continued at ambient temperature for 15 minutes. The insolublesubstance was collected by filtration and washed with methylenechloride. The washings and the filtrate were combined and then extractedthree times with 5% hydrochloric acid. After the combined extracts werewashed with diethyl ether, thereto was added methylene chloride,followed by adjusting to pH 7.5 with 28% aqueous ammonium hydroxide. Theseparated methylene chloride solution was washed with a saturatedaqueous sodium chloride and then dried over magnesium sulfate. Removalof the solvent gave an oil of tert-butyl 4-aminooxycrotonate (11.03 g).

IR (Film): 3340, 3250, 2980, 2940, 1720, 1660 cm⁻¹.

NMR δppm (DMSO-d₆): 1.43 (9H, s), 4.18 (2H, m), 5.85 (1H, m), 6.14 (2H,broad s), 6.52-7.06 (1H, m).

PREPARATION 43

To tert-butyl 4-aminooxycrotonate (10.0 g) were added ethanol (150 ml)and water (150 ml), followed by gradually adding(2-formamidothiazol-4-yl)glyoxylic acid (11.0 g) with stirring. Duringthe addition, the mixture was adjusted to pH 5 to 5.5 with 10% aqueoussodium hydroxide, and the stirring was continued at ambient temperaturefor 2 hours. After removal of the ethanol, to the remaining aqueoussolution was added ethyl acetate, followed by adjusting to pH 7.5 with10% aqueous sodium hydroxide. The aqueous layer was separated and washedwith ethyl acetate. Thereto was further added ethyl acetate, followed byadjusting to pH 2.0 with 10% hydrochloric acid. The separated organiclayer was washed with a saturated aqueous sodium chloride and then driedover magnesium sulfate. Removal of the solvent gave a residue, which waspulverized with n-hexane and tetrahydrofuran, and collected byfiltration. To this substance were added ethanol (50 ml) and water (30ml), followed by adjusting to pH 7.5 with 10% aqueous sodium hydroxide.The precipitated substance was collected by filtration, washed with amixed solvent of water and ethanol (1:1 by volume), followed by additionof water and ethyl acetate, and adjusting to pH 2.0 with 10%hydrochloric acid. The organic layer was separated, washed with asaturated aqueous sodium chloride and then dried over magnesium sulfate.Removal of the solvent gave a residue, which was pulverized withn-hexane and tetrahydrofuran to obtain2-(trans-3-tert-butoxycarbonylallyloxyimino)-2-(2-formamidothiazol-4-yl)aceticacid (syn isomer) (12.01 g).

IR (Nujol): 3150, 1720, 1650 cm⁻¹.

NMR δppm (DMSO-d₆): 1.47 (9H, s), 4.89 (2H, m), 5.96 (1H, m), 6.69-7.16(1H, m), 7.60 (1H, s), 8.57 (1H, s), 12.72 (1H, broad s).

PREPARATION 44

To a solution of2-(trans-3-tert-butoxycarbonylallyloxyimino)-2-(2-formamidothiazol-4-yl)aceticacid (syn isomer) (8.0 g) in ethyl acetate (60 ml) and ethanol (60 ml)was added 10% palladium on carbon (4.0 g) moistened in water (3 ml) in astream of nitrogen atmosphere, followed by subjecting to catalyticreduction under atmospheric pressure for 4 hours. After the catalyst wasremoved by filtration, the filtrate was evaporated. To the residue wereadded water and ethyl acetate, followed by adjusting to pH 7.5 with asaturated aqueous sodium bicarbonate. The separated aqueous layer waswashed with ethyl acetate, and thereto was added ethyl acetate, followedby adjusting to pH 2.0 with 10% hydrochloric acid. The separated organiclayer was washed with a saturated aqueous sodium chloride and then driedover magnesium sulfate. Removal of the solvent gave a residue, which wascrystallized from n-hexane and collected by filtration to obtain2-(3-tert-butoxycarbonylpropoxyimino)-2-(2-formamidothiazol-4-yl)aceticacid (syn isomer) (1.80 g).

NMR δppm (DMSO-d₆): 1.44 (9H, s), 1.93 (2H, m), 2.33 (2H, t, J=6.0 Hz),4.20 (2H, t, J=6.0 Hz), 7.61 (1H, s), 8.61 (1H, s), 12.63 (1H, broad s).

PREPARATION 45

Ethyl (2-formamido-5-chlorothiazol-4-yl)glyoxylate (14.5 g) was added toa solution of 1N aqueous potassium hydroxide (110 ml) at ambienttemperature, and the mixture was stirred for 10 minutes to prepare thesolution of potassium (2-formamido-5-chlorothiazol-4-yl)glyoxylate.After this solution was adjusted to pH 2 with 10% hydrochloric acidunder ice-cooling, thereto were added pyridine (20 ml) and a solution oftert-butyl 2-aminooxyacetate (10.3 g) in tetrahydrofuran (50 ml),followed by stirring at ambient temperature for 5 hours. After thereaction mixture was washed with ethyl acetate, the remaining aqueoussolution was adjusted to pH 1.5 with 10% hydrochloric acid and extractedwith ethyl acetate. The extract was washed with an aqueous sodiumchloride and then dried over magnesium sulfate. Removal of the solventgave2-tert-butoxycarbonylmethoxyimino-2-(2-formamido-5-chlorothiazol-4-yl)aceticacid (syn isomer) (8.5 g).

IR (Nujol): 3150, 1725, 1690, 1650, 1560, 1530 cm⁻¹.

NMR δppm (DMSO-d₆): 1.47 (9H, s), 4.75 (2H, s), 8.7 (1H, s), 12.8 (1H,s).

PREPARATION 46

1N Aqueous sodium hydroxide (49 ml) was added to a suspension ofS-methyl (6-formamidopyridin-2-yl)-thioglyoxylate (10 g) in methanol(100 ml), and the mixture was stirred at ambient temperature for 50minutes to prepare the solution of sodium(6-formamidopyridin-2-yl)glyoxylate. To this solution was addedtert-butyl 2-aminooxyacetate (7.2 g) and the mixture was adjusted to pH3 to 4 with 6N hydrochloric acid, followed by stirring at ambienttemperature for 4 hours. The reaction mixture was neutralized with anaqueous sodium bicarbonate and concentrated to half of the originalvolume under reduced pressure, followed by washing with ethyl acetateand adjusting to pH 1.5 with 10% hydrochloric acid.

The resultant aqueous solution was extracted three times with ethylacetate, and the combined extracts were washed with a saturated aqueoussodium chloride and dried over magnesium sulfate. Removal of the solventgave 2-tert-butoxycarbonylmethoxyimino-2-(6-formamidopyridin-2-yl)aceticacid (syn isomer) (11.9 g), mp 162°-168° C.

IR (Nujol): 3180, 1741, 1673 cm⁻¹.

NMR δppm (DMSO-d₆): 1.47 (9H, s), 4.73 (2H, s), 7.3-8.3 (3H, m), 9.17(1H, broad s), 10.7 (1H, d, J=6 Hz).

PREPARATION 47

2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-tert-butoxycarbonylmethoxyiminoaceticacid (syn isomer), mp 150°-155° C. (dec.), was obtained by reactingS-methyl (5-formamido-1,2,4-thiadiazol-3-yl)thioglyoxylate with aqueoussodium hydroxide and then tert-butyl 2-aminooxyacetate according to asimilar manner to that of Preparation 46.

IR (Nujol): 3420, 3230, 3100, 1725, 1610, 1530 cm⁻¹.

NMR δppm (DMSO-d₆): 1.45 (9H, s), 4.70 (2H, s), 8.12 (2H, broad s).

PREPARATION 48

To an aqueous solution (27 ml) of sodium hydroxide (2.1 g) were addedethyl 2-(5-tritylamino-2H-tetrazol-2-yl)acetate (14.2 g), methanol (50ml) and tetrahydrofuran (100 ml), and the mixture was stirred at 40° C.for 2 hours. After the organic solvent was removed by evaporation, tothe residue were added water (50 ml) and ethyl acetate (50 ml), followedby separating out the aqueous layer. Thereto was added ethyl acetate(100 ml) and then adjusted to pH 1.5 with 10% hydrochloric acid. Theaqueous solution was washed with an aqueous sodium chloride (50 ml) anddried over magnesium sulfate. Removal of the solvent gave a residue,which was pulverized with diisopropyl ether to obtain2-(5-tritylamino-2H-tetrazol-2-yl)acetic acid (9.0 g).

IR (Nujol): 3350, 1860, 1730, 1570, 1530 cm⁻¹.

NMR δppm (DMSO-d₆): 5.15 (2H, s), 7.0-7.58 (15H, m), 7.83 (1H, s).

PREPARATION 49

Vilsmeier reagent was prepared from phosphorus oxychloride (14.8 g) andN,N-dimethylformamide (7.07 g) in ethyl acetate (50 ml) in aconventional manner.2-(tert-Butoxycarbonylmethoxyimino)-2-(formamidothiazol-4-yl)acetic acid(syn isomer) (29 g) was added to the stirred suspension of Vilsmeierreagent in ethyl acetate (250 ml) under ice-cooling and stirred for 30minutes at same temperature to prepare an activated acid solution. Onthe other hand, benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylatemonohydrochloride (36.1 g) was dissolved in a solution oftrimethylsilylacetamide (63 g) in ethyl acetate (400 ml). To thissolution was added the above activated acid solution at -12° C. and themixture was stirred for an hour at -20° to 0° C. Water was added to thereaction mixture at 0° C. The organic layer was separated, washed with asaturated aqueous sodium bicarbonate and an aqueous sodium chloride. Thesolution was dried over magnesium sulfate and evaporated under reducedpressure. The residue was pulverized with diethyl ether to givebenzhydryl7-[2-tert-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate(syn isomer) (49.7 g).

IR (Nujol): 3200, 1780, 1720, 1680, 1540 cm⁻¹.

NMR δppm (DMSO-d6): 1.42 (9H, s), 3.66 (2H, q, J=18 Hz), 4.43 (2H, s),4.64 (2H, s), 5.27 (1H, d, J=5 Hz), 5.98 (1H, d d, J=5 Hz, 8 Hz), 6.96(1H, s), 7.00-7.60 (11H, m), 8.50 (1H, s), 9.64 (1H, d, J=8 Hz), 12.58(1H, broad s).

PREPARATION 50

Sodium iodide (4.5 g) was added to a solution of benzhydryl7-[2-tert-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate(7.6 g) in acetone (70 ml) and the mixture was stirred for 2.5 hours atambient temperature. The reaction mixture was poured into a mixture ofethyl acetate (200 ml) and an aqueous sodium chloride (100 ml), and theorganic layer was separated out, washed with 10% aqueous sodiumthiosulfate and an aqueous sodium chloride. The solution was dried overmagnesium sulfate and evaporated to give a residue. This residue andtriphenylphosphine (5.2 g) were dissolved in ethyl acetate (100 ml) andstirred for an hour. The precipitates were collected by filtration,washed with ethyl acetate and dried to give[4-benzhydryloxycarbonyl-{7-(2-tert-butoxycarbonylmethoxyimino)-2-(2-formamidothiazol-4-yl)acetamido}-3-cephem-3-ylmethyl]-triphenyl-phosphoniumiodide (6.5 g).

IR (Nujol): 1785, 1710, 1680, 1530 cm⁻¹.

PREPARATION 51

2-(4-Aminopyrimidin-2-yl)-2-tert-butoxycarbonylmethoxyiminoacetic acid(syn isomer) (9.7 g) was obtained by reacting S-methyl(4-formamidopyrimidin-2-yl)thioglyoxylate (20.0 g) with 1N aqueoussodium hydroxide (80 ml) and then tert-butyl 2-aminooxyacetate (15 g)according to a similar manner to that of Preparation 46.

IR (Nujol): 3200, 1750, 1718, 1693 cm⁻¹.

PREPARATION 52

A solution of ethyl 3-amino-3-thioxopropionate (73.5 g) in diethyl ether(100 ml) was added to a solution of bromopiruvic acid (88.5 g) indiethyl ether (300 ml) and stirred for 15 hours at ambient temperature.The precipitates were collected by filtration and added to a mixture ofwater (500 ml) and diethyl ether (300 ml) and then adjusted to pH 7.5with 20% aqueous sodium carbonate. The separated aqueous solution wasadjusted to pH 1.0 with conc. hydrochloric acid and extracted withdiethyl ether. The diethyl ether layer was dried over magnesium sulfateand evaporated. The residue was washed with diisopropyl ether to giveethyl 2-(4-carboxythiazol-2-yl)acetate (57.1 g).

IR (Nujol): 3100, 2870-2400, 1730, 1670 cm⁻¹.

NMR δppm (DMSO-d6): 1.28 (3H, t, J=7 Hz), 4.23 (2H, q, J=7 Hz), 4.30(2H, s), 8.50 (1H, s).

PREPARATION 53

Triethylamine (10.1 g) was added to a solution of ethyl2-(4-carboxythiazol-2-yl)acetate (21.5 g) in tert-butanol (200 ml) anddiphenylphosphorous azide (27.5 g) and the mixture was refluxed andstirred for 2 hours. After removing the solvent from the reactionmixture, the residue was dissolved in ethyl acetate (500 ml). The ethylacetate was washed with water, a saturated aqueous sodium bicarbonateand an aqueous sodium chloride, and then dried over magnesium sulfate.The solvent was removed by evaporation, and the residue was washed withdiisopropyl ether and collected by filtration to give ethyl2-(4-tert-butoxycarbonylaminothiazol-2-yl)-acetate (19.1 g).

IR (Nujol): 3180, 1730, 1710, 1530 cm⁻¹.

NMR δppm (DMSO-d6): 1.23 (3H, t, J=7 Hz), 1.50 (9H, s), 4.07 (2H, s),4.15 (2H, q, J=7 Hz), 7.15 (1H, s), 10.00 (1H, s).

PREPARATION 54

Ethyl 2-(4-tert-butoxycarbonylaminothiazol-2-yl)-acetate (5.1 g) wasadded to a solution of selenium dioxide (2.96 g) in dioxane (60 ml) andwater (2 ml) at 110° C. and stirred for 4.5 hours at 110° C. The mixturewas evaporated and the residue was dissolved in ethyl acetate and water.The separated ethyl acetate layer was washed with an aqueous sodiumchloride and dried over magnesium sulfate. After removing the solvent,the residue was subjected to column chromatography on silica gel andeluted with methylene chloride. The fraction containing an objectcompound was evaporated to give ethyl(4-tert-butoxycarbonylaminothiazol-2-yl)glyoxylate (4.2 g).

IR (Film): 3250, 3150, 1720, 1680 cm⁻¹.

NMR δppm (CDCl₃): 1.42 (3H, t, J=7 Hz), 1.52 (9H, s), 4.44 (2H, q, J=7Hz), 7.89 (1H, s), 8.28 (1H, s).

PREPARATION 55

A solution of sodium hydroxide (2.05 g) in water (30 ml) was added to asolution of ethyl (4-tert-butoxycarbonylaminothiazol-2-yl)glyoxylate(7.7 g) in methanol (20 ml) and stirred for 1 hour at ambienttemperature. The mixture was adjusted to pH 7.0 with 10% hydrochloricacid and washed with diethyl ether. The separated aqueous layer wasadjusted to pH 2.0 with 10% hydrochloric acid and extracted with diethylether. The diethyl ether layer was washed with an aqueous sodiumchloride and dried over magnesium sulfate. The solvent was removed byevaporation, and the resultant(4-tert-butoxycarbonylaminothiazol-2-yl)glyoxylic acid was dissolved inmethanol (20 ml). On the other hand, a solution of 1N-sodium methylatein methanol (25 ml) was added to a solution of methoxylaminehydrochloride (2.35 g) in methanol (20 ml) and phenolphtharain indicator(2-3 drops), and stirred for 30 minutes. The insoluble material wasfiltered off, and the filtrate was added to the above solution andstirred for 2 hours at ambient temperature. The diisopropyl ether wasadded to the reaction mixture and the precipitates were collected byfiltration to give2-methoxyimino-2-(4-tert-butoxycarbonylaminothiazol-2-yl)acetic acid(syn isomer) (3.6 g).

IR (Nujol): 3250, 3150, 1730, 1640, 1630 cm⁻¹.

NMR δ ppm (DMSO-d6): 1.45 (9H, s), 3.97 (3H, s), 7.37 (1H, s), 10.33(1H, s).

PREPARATION OF THE OBJECT COMPOUNDS EXAMPLE 1

To a solution ofN-tert-butoxycarbonyl-2-(3-methanesulfonamidophenyl)-D-glycine (4.13 g)and triethylamine (1.2 g) in tetrahydrofuran (40 ml) was added dropwisea solution of ethyl chloroformate (1.3 g) in tetrahydrofuran (4 ml) at-5° to -4° C. over a period of 5 minutes, followed by stirring at -5° to2° C. for an hour to give a solution of the activated acid.

On the other hand, benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylatehydrochloride (4.3 g) and trimethylsilylacetamide (7.9 g) were added toethyl acetate (50 ml), and the mixture was stirred for 5 minutes.

To the resultant solution was added the solution of the activated acidprepared above, and the mixture was stirred at -30° to 0° C. for 2hours. After addition of ethyl acetate (150 ml) and water, the organiclayer was separated out. The remaining aqueous solution was extractedwith ethyl acetate, and the combined ethyl acetate solution was washedwith a saturated aqueous solution of sodium bicarbonate and an aqueoussolution of sodium chloride, dried over anhydrous magnesium sulfate, andthen evaporated. The residue was washed with diethyl ether and collectedby filtration to give benzhydryl7-[N-tert-butoxycarbonyl-2-(3-methanesulfonamidophenyl)-D-glycinamido]-3-vinyl-3-cephem-4-carboxylate(5.3 g). The washings of diethyl ether were evaporated to dryness torecover the same compound (0.7 g). Total yield is 6.0 g.

I.R. (Nujol): 3340, 3280, 3250, 1790, 1710, 1690, 1670, 1520 cm⁻¹.

NMR δppm (DMSO-d₆): 1.37 (9H, s), 2.97 (3H, s), 3.65 (2H, q, J=16 Hz),5.12 (1H, d, J=5 Hz), 5.15 (1H, s), 5.25 (1H, d, J=10 Hz), 5.58 (1H, d,J=17 Hz), 5.78 (1H, dd, J=5 Hz, 8 Hz), 6.70 (1H, dd, J=10 Hz, 17 Hz),6.93 (1H, s), 7.00-7.60 (14H, m), 9.20 (1H, d, J=8 Hz), 9.70 (1H, s).

EXAMPLE 2

To a suspension of 2-(3-methanesulfonamidophenyl)-D-glycine (2.44 g) inmethylene chloride (25 ml) was blown hydrogen chloride gas at 5° to 10°C. over a period of 5 minutes. After addition of phosphorus pentoxide(3.1 g), the mixture was stirred at 0° to 10° C. for 5 hours. Theprecipitated solid therein was collected by filtration, washed withmethylene chloride (5 ml) and then dried to give the residue (2.7 g).This residue was added to a solution of7-amino-3-vinyl-3-cephem-4-carboxylic acid (1.8 g) andtrimethylsilylacetamide (6.3 g) in methylene chloride (30 ml) at -15° C.with stirring, and the stirring was continued at -5° to 0° C. for 3hours. To the reaction mixture was added water (30 ml) and shaken for awhile. After separating out the aqueous layer, it was adjusted to pH5with 20 % aqueous solution of sodium carbonate and evaporated to drynessunder reduced pressure to give the solid, which was chromatographed on anonionic adsorption resin "Diaion HP-20" (120 ml). After washing withwater, elution was carried out with 30% isopropyl alcohol, and thefractions containing the desired compound were collected and evaporatedunder reduced pressure. The residue obtained was lyophilized to give7-[2-(3-methanesulfonamidophenyl)-D-glycinamido]-3-vinyl-3-cephem-4-carboxylicacid (0.47 g).

I.R. (Nujol): 3300-3150, 1760, 1685, 1605 cm⁻¹.

EXAMPLE 3

To a suspension of benzhydryl7-[N-tert-butoxycarbonyl-2-(3-methanesulfonamidophenyl)-D-glycinamido]-3-vinyl-3-cephem-4-carboxylate(5.0 g) in methylene chloride (50 ml) were added anisole (6.0 g) andtrifluoroacetic acid (16.0 g) under ice-cooling, and the mixture wasstirred at ambient temperature for an hour. After removal of thesolvent, to the residue were added ice-water and ethyl acetate, followedby adjusting to pH 7.5 with an aqueous solution of sodium carbonate. Theaqueous layer was separated out, washed with ethyl acetate and thenadjusted to pH 2.5 with 10% hydrochloric acid. After washing with ethylacetate, the aqueous solution was adjusted to pH 6 with an aqueoussolution of sodium bicarbonate, followed by removing the organic solventtherefrom completely. The resultant aqueous solution was adjusted to pH3.6 with 10% hydrochloric acid and then subjected to columnchromatography using non-ionic adsorption resin "Diaion HP-20" (TradeMark, manufactured by Mitsubishi Chemical Industries Ltd.) (120 ml).After washing it with water (240 ml), elution was carried out with 30%isopropyl alcohol (180 ml) and the eluate was evaporated and lyophilizedto give7-[2-(3-methanesulfonamidophenyl)-D-glycinamido]-3-vinyl-3-cephem-4-carboxylicacid (1.4 g).

I.R. (Nujol): 3300-3150, 1760, 1685, 1605 cm⁻¹.

NMR δppm (D₂ O): 3.08 (3H, s), 3.47 (2H, s), 4.73 (1H, d, J=4 Hz), 5.10(1H, d, J=4 Hz), 5.32 (1H, s), 5.33 (1H, d, J=17 Hz), 5.63 (1H, d, J=4Hz), 6.73 (1H, dd, J=11 Hz, 17 Hz), 7.33 (4H, s)

EXAMPLE 4

(1) To a solution of7-[2-(3-methanesulfonamidophenyl)-D-glycinamido]-3-vinyl-3-cephem-4-carboxylicacid (3.6 g) in water (50 ml) was added sodium bicarbonate (0.668 g) andthe solution was filtered. The filtrate was lyophilized to give sodium7-[2-(3-methanesulfonamidophenyl)-D-glycinamido]-3-vinyl-3-cephem-4-carboxylate(3.69 g).

(2) To the compound (1.5 g) obtained above in N,N-dimethylformamide (15ml) was added a solution of iodomethyl pivalate (0.76 g) inN,N-dimethylformamide (2 ml) under ice-cooling, and the mixture wasstirred at the same temperature for 10 minutes. After addition of ethylacetate (80 ml), the reaction mixture was washed twice with water (80ml), three times with 5% aqueous solution of sodium bicarbonate (80 ml)and three times with an aqueous solution of sodium chloride in turn, andthen dried over anhydrous magnesium sulfate. Removal of the solvent gavea residue, which was pulverized with diisopropyl ether to givepivaloyloxymethyl7-[2-(3-methanesulfonamidophenyl)-D-glycinamido]-3-vinyl-3-cephem-4-carboxylate(0.61 g).

I.R. (Nujol): 1775, 1745, 1670 cm⁻¹.

EXAMPLE 5

To a solution of diketene (1.26 g) in carbon tetrachloride (12 ml) wasadded a solution of bromine (2.40 g) in carbon tetrachloride (3 ml) at-30° to -25° C., and the mixture was stirred at the same temperature forhalf an hour to prepare a solution of 4-bromoacetoacetyl bromide. Thissolution was added dropwise to a solution of benzhydryl7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (6.43 g) andtrimethylsilylacetamide (7.82 g) in ethyl acetate (129 ml) at -30° C.with stirring, and the stirring was continued at -30° to -10° C. for 2hours. To the reaction mixture were added water at -20° C. and ethylacetate, followed by separating out the organic layer, which was washedwith water, an aqueous solution of sodium bicarbonate and a saturatedaqueous solution of sodium chloride in turn, dried over anhydrousmagnesium sulfate and then evaporated. The residue obtained wasdissolved in a mixture of ethanol (100 ml) and tetrahydrofuran (100 ml),and to this solution was added thiourea (3.42 g), followed by stirringat ambient temperature for an hour. After evaporation of the reactionmixture, to the residue were added water and ethyl acetate, and thenadjusted to pH 7 with sodium bicarbonate. The separated ethyl acetatelayer was washed with an aqueous solution of sodium chloride, dried overanhydrous magnesium sulfate and then evaporated under reduced pressureto give benzhydryl7-[2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate(6.89 g).

IR (Nujol): 1760, 1740, 1650, 1610 cm⁻¹.

NMR δppm (DMSO-d₆): 3.47 (2H, broad s), 3.80 (2H, m), 5.27 (1H, d, J=5Hz), 5.35 (1H, d, J=11 Hz), 5.68 (1H, d, J=18 Hz), 5.87 (1H, dd, J=5 Hz,8 Hz), 6.33 (1H, s), 6.85 (1H, dd, J=11 Hz, 18 Hz), 6.93 (2H, m), 7.02(1H, s), 7.43 (10H, s), 9.00 (1H, d, J=8 Hz).

EXAMPLE 6

Pivaloyloxymethyl7-[2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate wasobtained according to the similar manner to that of Example 5

IR (Nujol): 1770, 1750, 1650 cm⁻¹.

EXAMPLE 7

To a solution of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylatehydrochloride (1.9 g) and trimethylsilylacetamide (4.6 g) in ethylacetate (30 ml) was added at -30° C. a solution of the activated acid,which was prepared by stirring a mixture of2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer) (1.1g), phosphorus oxychloride (0.81 g), N,N-dimethylformamide (0.39 g) andethyl acetate (20 ml) for half an hour under ice-cooling, and themixture was stirred at -30° to -10° C. for an hour. After addition ofethyl acetate (100 ml) and water (50 ml), the organic layer wasseparated out, washed with a saturated aqueous solution of sodiumbicarbonate and an aqueous solution of sodium chloride, dried overanhydrous magnesium sulfate and then evaporated to dryness to givebenzhydryl7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (2.4 g).

IR (Nujol): 3250, 1780, 1710, 1700, 1660, 1540 cm⁻¹.

NMR δppm (DMSO-d₆): 3.78 (2H, m), 3.95 (3H, s), 5.30 (1H, d, J=11 Hz),5.32 (1H, d, J=5 Hz), 5.66 (1H, d, J=17 Hz), 5.96 (1H, dd, J=5 Hz, 8Hz), 6.82 (1H, dd, J=11 Hz, 17 Hz), 7.00 (1H, s), 7.17-7.73 (11H, m),8.57 (1H, s), 9.80 (1H, d, J=8 Hz), 12.7 (1H, broad s).

EXAMPLE 8

Benzhydryl7-[2-(2-formamidothiazol-4-yl)-2-allyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (3.1 g) was obtained by reacting benzhydryl7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (2.15 g) with2-(2-formamidothiazol-4-yl)-2-allyloxyiminoacetic acid (syn isomer)(1.53 g) according to the similar manner to that of Example 7.

IR (Nujol): 3250, 1760, 1710, 1690, 1660, 1530 cm⁻¹.

NMR δppm (DMSO-d₆): 3.75 (2H, q, J=18 Hz), 4.65 (2H, d, J=5 Hz),5.00-6.3 (7H, m), 6.77 (1H, dd, J=11 Hz, 18 Hz), 6.97 (1H, s), 7.17-7.63(11H, m), 8.53 (1H, s), 9.78 (1H, d, J=8 Hz), 12.7 (1H, broad s)

EXAMPLE 9

Benzhydryl7-[2-(2-formamidothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (1.3 g) was obtained by reacting benzhydryl7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (1.0 g) with2-(2-formamidothiazol-4-yl)-2-propargyloxyiminoacetic acid (syn isomer)(0.71 g) according to the similar manner to that of Example 7.

IR (Nujol): 3250, 1780, 1720, 1690, 1660, 1550 cm⁻¹.

NMR δppm (DMSO-d₆): 3.38 (1H, m), 3.82 (2H, q, J=18 Hz), 4.82 (2H, m),5.33 (1H, d, J=5 Hz), 5.35 (1H, d, J=11 Hz), 5.55 (1H, d, J=18 Hz), 5.98(1H, dd, J=5 Hz, 8 Hz), 6.85 (1H, dd, J=11 Hz, 18 Hz), 7.02 (1H, s),7.17-7.82 (10H, m), 7.55 (1H, s), 8.62 (1H, s), 9.80 (1H, d, J=8 Hz),12.60 (1H, broad s).

EXAMPLE 10

Benzhydryl7-[(2-formamidothiazol-4-yl)glyoxylamido]-3-vinyl-3-cephem-4-carboxylate(6.1 g) was obtained by reacting benzhydryl7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (6.0 g) with(2-formamidothiazol-4-yl)-glyoxylic acid (3.93 g) according to thesimilar manner to that of Example 7, mp 141°-144° C. (dec.).

IR (Nujol): 3150, 1780, 1720, 1695, 1670, 1620, 1520 cm⁻¹.

NMR δppm (DMSO-d₆): 3.78 (2H, q, J=18 Hz), 5.33 (1H, d, J=5 Hz), 5.33(1H, d, J=11 Hz), 5.68 (1H, d, J=17 Hz), 5.93 (1H, dd, J=5 Hz, 8Hz),6.87 (1H, dd, J=11 Hz), 17 Hz), 7.00 (1H, s), 7.20-7.67 (10H, m), 8.50(1H, s), 8.63 (1H, s), 9.97 (1H, d, J=8 Hz), 12.82 (1H, broad s).

The compounds described in the following Examples 11 to 20 were obtainedby reacting the 7-amino-3-vinylcephalosporanic acid derivatives with thecorresponding acid according to the similar manner to that of Example 7.

EXAMPLE 11

7-[2-(2-Aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylic acid

IR (Nujol): 3260, 1760, 1650 cm⁻¹.

EXAMPLE 12

7-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid hydrochloride (syn isomer)

IR (Nujol): 3260, 1775, 1720, 1660, 1645, 1600, 1550 cm⁻¹.

EXAMPLE 13

7-[2-(2-Aminothiazol-4-yl)-2-allyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer)

IR (Nujol): 3250, 1770, 1655, 1605, 1545 cm⁻¹.

EXAMPLE 14

7-[2-(2-Aminothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer)

IR (Nujol): 3250, 1760, 1680, 1620, 1530 cm⁻¹.

EXAMPLE 15

7-[(2-Aminothiazol-4-yl)glyoxylamido]-3-vinyl-3-cephem-4-carboxylic acid

IR (Nujol): 3300, 3200-3100, 1780, 1660, 1610, 1520 cm⁻¹.

EXAMPLE 16

Pivaloyloxymethyl7-[2-(2-aminothiazol-4-yl)-acetamido]-3-vinyl-3-cephem-4-carboxylate

IR (Nujol): 1770, 1750, 1650 cm⁻¹.

EXAMPLE 17

Pivaloyloxymethyl7-[2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1770, 1740, 1670 cm⁻¹.

EXAMPLE 18

Pivaloyloxymethyl7-[2-(2-aminothiazol-4-yl)glyoxylamido]-3-vinyl-3-cephem-4-carboxylate

IR (Nujol): 1775, 1745, 1660 cm⁻¹.

EXAMPLE 19

Hexanoyloxymethyl7-[2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1770, 1650 cm⁻¹.

EXAMPLE 20

Hexanoyloxymethyl7-[(2-aminothiazol-4-yl)-glyoxylamido]-3-vinyl-3-cephem-4-carboxylate

IR (Nujol): 1770, 1660 cm⁻¹.

EXAMPLE 21

To a solution of benzhydryl7-[2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate(6.79 g) in methylene chloride (68 ml) were added trifluoroacetic acid(29.1 g) and anisole (11.02 g) at 0° C., and the mixture was stirred atambient temperature for 65 minutes. After the reaction mixture wasevaporated, to the residue were added ethyl acetate and water, followedby adjusting to pH 7 with an aqueous solution of sodium bicarbonate. Theseparated aqueous solution was adjusted to pH 3.0 with 10% hydrochloricacid, and the precipitated substance was collected by filtration to give7-[2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylic acid(1.88 g), mp 104°-116° C. (dec.).

IR (Nujol): 3260, 1760, 1650 cm⁻¹.

NMR δppm (DMSO-d₆): 3.47 (2H, s), 3.77 (2H, q, J=18 Hz), 5.18 (1H, d,J=5 Hz), 5.35 (1H, d, J=11 Hz), 5.62 (1H, d, J=18 Hz), 5.73 (1H, dd, J=5Hz, 8 Hz), 6.33 (1H, s), 6.75-7.15 (2H, m), 6.98 (1H, dd, J=11 Hz, 18Hz), 8.95 (1H, d, J=8 Hz).

EXAMPLE 22

To a suspension of benzhydryl7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (2.3 g) in methylene chloride (40 ml) were added anisole(3.3 g) and trifluoroacetic acid (8.7 g) under ice-cooling withstirring, and the stirring was continued at ambient temperature for 75minutes. After evaporation of the reaction mixture, to the residue wereadded water and ethyl acetate, followed by adjusting to pH 7 with asaturated aqueous solution of sodium bicarbonate. To the separatedaqueous solution was added ethyl acetate, followed by adjusting to pH 2with 10% hydrochloric acid. The ethyl acetate layer was separated out,washed with an aqueous solution of sodium chloride, dried over anhydrousmagnesium sulfate and then evaporated to dryness to give a residue,which was washed with diethyl ether to obtain7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (1.45 g).

IR (Nujol): 3250, 1770, 1690, 1650, 1540 cm⁻¹.

NMR δppm (DMSO-d₆): 3.70 (2H, q, J=17 Hz), 3.88 (3H, s), 5.20 (1H, d,J=5 Hz), 5.30 (1H, d, J=11 Hz), 5.55 (1H, d, J=18 Hz), 5.82 (1H, dd, J=5Hz, 8 Hz), 6.93 (1H, dd, J=11 Hz, 18 Hz), 7.45 (1H, s), 8.52 (1H, s),9.73 (1H, d, J=8 Hz).

EXAMPLE 23

7-[2-(2-Formamidothiazol-4-yl)-2-allyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (1.7 g) was obtained by reacting benzhydryl7-[2-(2-formamidothiazol-4-yl)-2-allyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (3.0 g) with trifluoroacetic acid (10.8 g) in the presenceof anisole (4.0 g) according to the similar manner to that of Example22.

IR (Nujol): 3250, 1770, 1680 (shoulder), 1650, 1530 cm⁻¹.

NMR δppm (DMSO-d₆): 3.67 (2H, q, J=18 Hz), 4.60 (2H, d, J=4 Hz),4.83-6.33 (7H, m), 6.90 (1H, dd, J=11 Hz, 18 Hz), 7.38 (1H, s), 8.48(1H, s), 9.70 (1H, d, J=8 Hz), 12.62 (1H, broad s).

EXAMPLE 24

7-[2-(2-Formamidothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (0.77 g) was obtained by reacting benzhydryl7-[2-(2-formamidothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (1.2 g) with trifluoroacetic acid (4.4 g) in the presenceof anisole (1.7 g) according to the similar manner to that of Example22.

IR (Nujol): 3250, 1780, 1680, 1660, 1550 cm⁻¹.

NMR δppm (DMSO-d₆): 3.52 (1H, m), 3.77 (2H, q, J=18 Hz), 4.80 (2H, m),5.27 (1H, d, J=5 Hz), 5.37 (1H, d, J=11 Hz), 5.62 (1H, d, J=18 Hz), 5.87(1H, dd, J=5 Hz, 8 Hz), 7.00 (1H, dd, J=11 Hz, 18 Hz), 7.50 (1H, s),8.57 (1H, s), 9.83 (1H, d, J=8 Hz), 12.77 (1H, broad s).

EXAMPLE 25

7-[(2-Formamidothiazol-4-yl)glyoxylamido]-3-vinyl-3-cephem-4-carboxylicacid (3.0 g) was obtained by reacting benzhydryl7-[(2-formamidothiazol-4-yl)-glyoxylamido]-3-vinyl-3-cephem-4-carboxylate(6.0 g) with trifluoroacetic acid (23.7 g) in the presence of anisole(9.0 g) according to the similar manner to that of Example 22.

NMR δppm (DMSO-d₆): 3.75 (2H, q, J=17 Hz), 5.27 (1H, d, J=5 Hz), 5.37(1H, d, J=11 Hz), 5.63 (1H, d, J=17 Hz), 5.83 (1H, dd, J=5 Hz, 8 Hz),7.00 (1H, dd, J=11 Hz, 17 Hz), 8.50 (1H, s), 8.65 (1H, s), 9.93 (1H, d,J=8 Hz), 12.8 (1H, broad s).

The compounds described in the following Examples 26 to 29 were obtainedby reacting benzhydryl ester of the corresponding cephalosporanic acidderivatives with trifluoroacetic acid in the presence of anisoleaccording to the similar manner to that of Example 22.

EXAMPLE 26

7-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid hydrochloride (syn isomer)

IR (Nujol): 3260, 1775, 1720, 1660, 1645, 1600, 1550 cm⁻¹.

EXAMPLE 27

7-[2-(2-Aminothiazol-4-yl)-2-allyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer)

IR (Nujol): 3250, 1770, 1655, 1605, 1545 cm⁻¹.

EXAMPLE 28

7-[2-(2-Aminothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3250, 1760, 1680, 1620, 1530 cm⁻¹.

EXAMPLE 29

7-[(2-Aminothiazol-4-yl)glyoxylamido]-3-vinyl-3-cephem-4-carboxylic acid

IR (Nujol): 3300, 3200-3100, 1780, 1660, 1610, 1520 cm⁻¹.

EXAMPLE 30

To a solution of7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (1.4 g) in methanol (30 ml) and tetrahydrofuran (20ml) was added conc. hydrochloric acid (1.0 ml), and the mixture wasstirred at ambient temperature for 2.7 hours. After evaporation of thereaction mixture, the residue was washed with tetrahydrofuran to give7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid hydrochloride (syn isomer) (1.2 g).

IR (Nujol): 3260, 1775, 1720, 1660, 1645, 1600, 1550 cm⁻¹.

NMR δppm (DMSO-d₆): 3.75 (2H, q, J=18 Hz), 4.00 (3H, s), 5.25 (1H, d,J=5 Hz), 5.35 (1H, d, J=11 Hz), 5.60 (1H, d, J=18 Hz), 5.80 (1H, dd, J=5Hz, 8 Hz), 6.98 (1H, dd, J=11 Hz, 18 Hz), 7.02 (1H, s), 9.87 (1H, d, J=8Hz).

EXAMPLE 31

A mixture of7-[2-(2-formamidothiazol-4-yl)-2-allyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (1.6 g) and conc. hydrochloric acid (1.5 ml) inmethanol (30 ml) was stirred at ambient temperature for 2 hours. Afterevaporation of the reaction mixture, thereto was added a saturatedaqueous solution of sodium bicarbonate, followed by removing theinsoluble substance by filtration. The filtrate was adjusted to pH 3with 10% hydrochloric acid, and the precipitated solid was collected byfiltration and washed with water to give7-[2-(2-aminothiazol-4-yl)-2-allyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (1.25 g).

IR (Nujol): 3250, 1770, 1655, 1605, 1545 cm⁻¹.

NMR δppm (DMSO-d₆): 3.75 (2H, q, J=18 Hz), 4.67 (2H, m), 5.00-6.5 (7H,m), 6.80 (1H, s), 7.00 (1H, dd, J=11 Hz, 18 Hz), 9.67 (1H, d, J=8 Hz).

EXAMPLE 32

7-[2-(2-Aminothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (0.5 g) was obtained by reacting7-[2-(2-formamidothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) with conc. hydrochloric acid (0.5 ml) in a mixture ofmethanol (14 ml) and tetrahydrofuran (4 ml) according to the similarmanner to that of Example 31.

IR (Nujol)): 3250, 1760, 1680, 1620, 1530 cm⁻¹.

NMR δppm (DMSO-d₆): 3.43 (1H, m), 3.68 (2H, q, J=18 Hz), 4.7 (2H, m),5.17 (1H, d, J=4 Hz), 5.28 (1H, d, J=12 Hz), 5.53 (1H, d, J=18 Hz), 5.73(1H, dd, J=4 Hz, 8 Hz), 6.83 (1H, s), 6.92 (1H, dd, J=12 Hz, 18 Hz),9.67 (1H, d, J=8 Hz).

EXAMPLE 33

7-[(2-Aminothiazol-4-yl)glyoxylamido]-3-vinyl-3-cephem-4-carboxylic acid(0.76 g) was obtained by reacting7-[(2-formamidothiazol-4-yl)glyoxylamido]-3-vinyl-3-cephem-4-carboxylicacid (1.23 g) with conc. hydrochloric acid (1.25 ml) in a mixture ofmethanol (25 ml) and tetrahydrofuran (10 ml) according to the similarmanner to that of Example 31.

IR (Nujol): 3300, 3200-3100, 1780, 1660, 1610, 1520 cm⁻¹.

NMR δppm (DMSO-d₆): 3.80 (2H, q, J=17 Hz), 5.28 (1H, d, J=5 Hz), 5.42(1H, d, J=11 Hz), 5.63 (1H, d, J=18 Hz), 5.82 (1H, dd, J=5 Hz, 8 Hz),7.05 (1H, dd, J=11 Hz, 18 Hz), 7.92 (1H, s), 9.58 (1H, d, J=8 Hz).

The compounds described in the following Examples 34 to 38 were obtainedby reacting the corresponding cephalosporanic acid derivatives havingformamido group with conc. hydrochloric acid according to the similarmanner to that of Example 31.

EXAMPLE 34

Pivaloyloxymethyl7-[2-(2-aminothiazol-4-yl)-acetamido]-3-vinyl-3-cephem-4-carboxylate

IR (Nujol): 1770, 1750, 1650 cm⁻¹.

EXAMPLE 35

Pivaloyloxymethyl7-[2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1770, 1740, 1670 cm⁻¹.

EXAMPLE 36

Pivaloyloxymethyl7-[(2-aminothiazol-4-yl)-glyoxylamido]-3-vinyl-3-cephem-4-carboxylate.

IR (Nujol): 1775, 1745, 1660 cm⁻¹.

EXAMPLE 37

Hexanoyloxymethyl7-[2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1770, 1650 cm⁻¹.

EXAMPLE 38

Hexanoyloxymethyl7-[(2-aminothiazol-4-yl)-glyoxylamido]-3-vinyl-3-cephem-4-carboxylate

IR (Nujol): 1770, 1660 cm⁻¹.

EXAMPLE 39

Sodium7-[2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate(1.36 g), which was prepared from7-[2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylic acid(1.33 g) and sodium bicarbonate (0.304 g), was dissolved inN,N-dimethylformamide (14 ml). To this solution was added iodomethylpivalate (0.932 g) in N,N-dimethylformamide (3 ml) under ice-cooling,followed by stirring at the same temperature for 10 minutes. Afteraddition of ethyl acetate (80 ml), the reaction mixture was washed twicewith water, three times with 5% aqueous solution of sodium bicarbonateand twice with an aqueous solution of sodium chloride in turn, driedover anhydrous magnesium sulfate, and then evaporated to dryness underreduced pressure to give a residue, which was pulverized withdiisopropyl ether to obtain pivaloyloxymethyl7-[2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (1.0g), mp 128°-132° C. (dec.).

IR (Nujol): 1770, 1750, 1650 cm⁻¹.

NMR δppm (DMSO-d₆): 1.18 (9H, s), 3.42 (2H, s), 3.80 (2H, q, J=17 Hz),5.18 (1H, d, J=5 Hz), 5.40 (1H, d, J=11 Hz), 5.68 (1H, d, J=17 Hz), 5.77(1H, dd, J=5 Hz, 8 Hz), 5.87 (2H, s), 6.30 (1H, s), 6.87 (2H, broad s),6.88 (1H, dd, J=11 Hz, 17 Hz), 8.93 (1H, d, J=8 Hz).

EXAMPLE 40

Privaloyloxymethyl7-[2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (1.64 g) was obtained by reacting sodium7-[2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (2 g) with iodomethyl pivalate (1.21 g) according to thesimilar manner to that of Example 39, mp 163°-185° C. (dec.).

IR (Nujol): 1770, 1740, 1670 cm⁻¹.

NMR Δppm (DMSO-d₆): 1.22 (9H, s), 3.5 (1H, s), 3.85 (2H, q, J=18 Hz),4.75 (1H, s), 5.35 (1H, d, J=5 Hz), 5.45 (1H, d, J=11 Hz), 5.70 (1H, d,J=18 Hz), 5.85 (1H, dd, J=5 Hz, 8 Hz), 5.92 (2H, s), 6.87 (1H, s), 6.88(1H, dd, J=11 Hz, 18 Hz), 7.32 (2H, m), 9.73 (1H, d, J=8 Hz).

EXAMPLE 41

Privaloyloxymethyl7-[(2-aminothiazol-4-yl)-glyoxylamido]-3-vinyl-3-cephem-4-carboxylate(0.94 g) was obtained by reacting sodium7-[(2-aminothiazol-4-yl)glyoxylamido]-3-vinyl-3-cephem-4-carboxylate(1.05 g) with iodomethyl pivalate (0.63 g) according to the similarmanner to that of Example 39, mp 108°-115° C.

IR (Nujol): 1775, 1745, 1660 cm⁻¹.

NMR δppm (DMSO-d₆): 1.12 (9H, s), 3.75 (2H, m), 5.22 (1H, d, J=5 Hz),5.38 (1H, d, J=11 Hz), 5.67 (1H, d, J=18 Hz), 5.78 (1H, dd, J=5 Hz, 8Hz), 5.83 (2H, s), 6.85 (1H, dd, J=11 Hz, 18 Hz), 7.35 (2H, broad s),7.83 (1H, s), 9.80 (1H, d, J=8 Hz).

EXAMPLE 42

To a solution of sodium7-[2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (2 g) in N,N-dimethylformamide (20 ml) was added a solutionof iodomethyl hexanoate (1.28 g) in N,N-dimethylformamide (4 ml) underice-cooling, and the mixture was stirred at the same temperature for 15minutes. To the reaction mixture was added ethyl acetate (80 ml),followed by washing twice with water, three times with 5% aqueoussolution of sodium bicarbonate and twice with a saturated aqueoussolution of sodium chloride. The resultant solution was dried overanhydrous magnesium sulfate and then evaporated to give a residue, whichwas pulverized with diisopropyl ether to obtain hexanoyloxymethyl7-[2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (1.85 g), mp 98°-109° C. (dec.).

IR (Nujol): 1770, 1650 cm⁻¹.

NMR δppm (DMSO-d₆): 0.87 (3H, t, J=8 Hz), 1.38 (6H, m), 2.53 (2H, m),3.47 (1H, s), 3.80 (2H, q, J=18 Hz), 4.72 (2H, s), 5.27 (1H, d, J=5 Hz),5.42 (1H, d, J=11 Hz), 5.70 (1H, d, J=18 Hz), 5.88 (3H, m), 6.80 (1H,s), 6.80 (1H, dd, J=11 Hz, 18 Hz), 7.25 (2H, broad s), 9.70 (1H, d, J=8Hz).

EXAMPLE 43

Hexanoyloxymethyl7-[(2-aminothiazol-4-yl)-glyoxylamido]-3-vinyl-3-cephem-4-carboxylate(0.96 g) was obtained by reacting sodium7-[(2-aminothiazol-4-yl)glyoxylamido]-3-vinyl-3-cephem-4-carboxylate(1.05 g) with iodomethyl hexanoate (0.666 g) according to the similarmanner to that of Example 42, mp 89°-94° C.

IR (Nujol): 1770, 1660 cm⁻¹.

NMR Δppm (DMSO-d₆), 0.82 (3H, s), 1.30 (6H, m), 2.30 (2H, t, J=6 Hz),3.77 (2H, m), 5.22 (1H, d, J=5 Hz), 5.37 (1H, d, J=11 Hz), 5.68 (1H, d,J=18 Hz), 5.77 (1H, dd, J=5 Hz, 8 Hz), 5.83 (2H, s), 6.88 (1H, dd, J=11Hz, 18 Hz), 7.37 (2H, m), 7.83 (1H, s), 9.78 (1H, d, J=8 Hz).

EXAMPLE 44

To a solution of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylatehydrochloride (4.3 g) and 2,6-lutidine (1.08 g) in methylene chloride(60 ml) were addedN-tert-butoxycarbonyl-2-(2-formamidothiazol-4-yl)glycine (3.0 g) andN,N'-dicyclohexylcarbodiimide (2.06 g) under ice-cooling with stirring,and the stirring was continued for the same temperature for an hour andat ambient temperature for additional 3.5 hours. After addition ofmethylene chloride (100 ml), the reaction mixture was washed withdiluted hydrochloric acid, followed by removal of the precipitatedsubstance by filtration. The filtrate was washed with a saturatedaqueous solution of sodium bicarbonate and an aqueous solution of sodiumchloride, dried over anhydrous magnesium sulfate and then evaporated togive a residue, which was pulverized with diethyl ether to obtainbenzhydryl7-[N-tert-butoxycarbonyl-2-(2-formamidothiazol-4-yl)glycinamido]-3-vinyl-3-cephem-4-carboxylate(5.7 g).

IR (Nujol): 3280, 1780, 1720, 1660, 1630, 1540 cm⁻¹.

NMR δppm (DMSO-d₆): 1.39 (9H, s), 3.65 (2H, q, J=17 Hz), 5.10 (1H, d,J=5 Hz), 5.19 (1H, s), 5.22 (1H, d, J=11 Hz), 5.59 (1H, d, J=18 Hz),5.74 (1H, dd, J=4 Hz, 8 Hz), 6.68 (1H, dd, J=11 Hz, 18 Hz), 6.93 (1H,s), 7.00-7.70 (12H, m), 9.24 (1H, d, J=8 Hz).

EXAMPLE 45

Benzhydryl7-[N-tert-butoxycarbonyl-2-{2-(2,2,2-trifluoroacetamido)thiazol-4-yl}-glycinamido]-3-vinyl-3-cephem-4-carboxylate(4.1 g) was obtained by reacting benzhydryl7-amino-3-vinyl-3-cephem-4-carboxylate (3.4 g) withN-tert-butoxycarbonyl-2-[2-(2,2,2-trifluoroacetamido)thiazol-4-yl]glycine(3.3 g) according to the similar manner to that of Example 44.

IR (Nujol): 3270, 1780, 1720, 1670, 1560 cm⁻¹.

NMR δppm: (DMSO-d₆): 1.43 (9H, s), 3.77 (2H, m), 5.13-6.00 (5H, m), 6.82(1H, dd, J=11 Hz), 18 Hz), 7.00 (1H, s), 7.10-7.70 (11H, m), 9.27 (1H,d, J=8 Hz).

EXAMPLE 46

To a suspension of benzhydryl7-[N-tert-butoxycarbonyl-2-(2-aminothiazol-4-yl)glycinamido]-3-vinyl-3-cephem-4-carboxylate(3.9 g) in methylene chloride (20 ml) were added trifluoroacetic acid(13.7 g) and anisole (3.8 g) under ice-cooling, and the mixture wasstirred at ambient temperature for an hour. After evaporation of thereaction mixture, to the residue were added water (100 ml) and ethylacetate, followed by adjusting to pH 7 with 2N aqueous solution ofsodium hydroxide. The precipitated solid was removed by filtration andthe aqueous layer was separated out. Thereto was added ethyl acetate,followed by adjusting to pH 5 with 10% hydrochloric acid. Afterseparating out the aqueous layer, the organic solvent was completelyremoved therefrom by evaporation, and then the resultant aqueoussolution was adjusted to pH 4 with 10% hydrochloric acid under cooling,followed by subjecting to column chromatography on a nonionic adsorptionresin "Diaion HP-20" (120 ml). After washing with water (270 ml),elution was carried out with 10% isopropyl alcohol and then 30%isopropyl alcohol, and the fractions containing the desired compoundwere collected and evaporated under reduced pressure to give a residue,which was lyophilized to obtain7-[2-(2-aminothiazol-4-yl)glycinamido]-3-vinyl-3-cephem-4-carboxylicacid (0.8 g).

IR (Nujol): 3400-3100, 1760, 1670, 1610, 1520 cm⁻¹

NMR δppm (D₂ O+NaHCO₃): 3.68 (2H, broad s), 5.08 (1H, s), 5.08 (1H, d,J=5 Hz), 5.25 (1H, d, J=11 Hz), 5.40 (1H, d, J=18 Hz), 5.70 (1H, d, J=5Hz), 6.73 (1H, s), 6.80 (1H, dd, J=11 Hz, 18 Hz).

EXAMPLE 47

A mixture of benzhydryl7-[N-tert-butoxycarboynyl-2-(2-formamidothiazol-4-yl)glycinamido]-3-vinyl-3-cephem-4-carboxylate(5.6 g) and conc. hydrochloric acid (2.6 ml) in methanol (60 ml) andtetrahydrofuran (15 ml) was stirred at ambient temperature for 2.5hours. The precipitated substance in the reaction mixture was collectedby filtration, and washed with a mixture of methanol and water (1:2 byvolume) and then water, followed by drying to give benzhydryl7-[N-tert-butoxycarbonyl-2-(2-aminothiazol-4-yl)-glycinamido]-3-vinyl-3-cephem-4-carboxylate(0.4 g).

IR (Nujol): 3300, 1770, 1710, 1650, 1620, 1570, 1510 cm⁻¹.

NMR δppm (DMSO-d₆): 1.40 (9H, s), 3.67 (2H, broad s), 5.00-6.00 (5H, m),6.47 (1H, s), 6.97 (1H, s), 6.67-7.67 (12H, m), 9.00 (1H, m).

EXAMPLE 48

A mixture of benzhydryl7-[N-tert-butoxycarbonyl-2-{2-(2,2,2-trifluoroacetamido)thiazol-4-yl}glycinamido]-3-vinyl-3-cephem-4-carboxylate(2.5 g) and sodium acetate (2.8 g) in tetrahydrofuran (20 ml), acetone(20 ml) and water (40 ml) was stirred at ambient temperature for 2hours. After the reaction mixture was evaporated, the residue wasextracted with ethyl acetate. The extract was washed with an aqueoussolution of sodium chloride, dried over anhydrous magnesium sulfate andthen evaporated to give a residue, which was subjected to columnchromatography on silica gel (50 g). Elution was carried out withmethylene chloride and then a mixture of methylene chloride and diethylether (9:1 by volume), and the fractions containing the desired compoundwere collected and evaporated to give benzhydryl7-[N-tert-butoxycarbonyl-2-(2-aminothiazol-4-yl)glycinamido]-3-vinyl-3-cephem-4-carboxylate(1.0 g).

IR (Nujol): 3300, 1770, 1710, 1650, 1620, 1570, 1510 cm⁻¹.

EXAMPLE 49

To a solution of7-[(2-aminothiazol-4-yl)-glyoxylamido]-3-vinyl-3-cephem-4-carboxylicacid (2.35 g) in methanol (100 ml) was added sodium borohydride (0.34 g)at 5°-10° C., and the mixture was stirred at the same temperature for 5minutes. After the reaction mixture was adjusted to pH 5 with 10%hydrochloric acid, the methanol was removed by evaporation, and theremained aqueous solution was adjusted to pH 5 with 10% hydrochloricacid, which was subjected to column chromatography on a nonionicadsorption resin "Diaion HP-20" (70 ml). After washing with water (140ml), elution was carried out with 30% isopropyl alcohol (140 ml), andthe fractions containing the desired compound were collected. Afterremoval of the isopropyl alcohol therefrom, the remained aqueoussolution was lyophilized to give7-[2-(2-aminothiazol-4-yl)-DL-glycolamido]-3-vinyl-3-cephem-4-carboxylicacid (2.01 g).

IR (Nujol): 1755, 1650 cm⁻¹.

NMR δppm (DMSO-d₆): 3.48 (2H, m), 3.83 (1H, broad s), 4.83 (1H, s), 4.98(1H, d, J=5 Hz), 5.2 (1H, d, J=11 Hz), 5.47 (1H, d, J=18 Hz), 5.5,5.53(1H, dd, J=5 Hz, 8 Hz), 6.37 (1H, s), 6.85 (2H, m), 7.07 (1H, dd, J=11Hz), 8.17,8.27 (1H, d, J=8 Hz).

EXAMPLE 50

7-[2-(2-Aminothiazol-4-yl)glycinamido]-3-vinyl-3-cephem-4-carboxylicacid was obtained by reacting 7-amino-3-vinyl-3-cephem-4-carboxylic acidwith 2-(2-aminothiazol-4-yl)glycine according to the similar manner tothat of Example 2.

IR (Nujol): 3400-3100, 1760, 1670, 1610, 1520 cm⁻¹.

EXAMPLE 51

A mixture of 2-(2-methanesulfonamidothiazol-4-yl)-acetic acid (2.6 g),N,N-dimethylformamide (0.88 g) and phosphorus oxychloride (1.85 g) inethyl acetate (10 ml) and tetrahydrofuran (20 ml) was stirred underice-cooling for 30 minutes. This solution was added to a solution ofbenzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (4.3 )and trimethylsilylacetamide (7.9 g) in ethyl acetate (50 ml) at -20° C.with stirring, and the stirring was continued at -20° to 0° C. for 2hours. After addition of water, tetrahydrofuran and ethyl acetate, thereaction mixture was adjusted to pH 7 with a saturated aqueous solutionof sodium bicarbonate. The precipitated substance was collected byfiltration to give benzhydryl7-[2-(2-methanesulfonamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate(3.6 g). After addition of ethyl acetate tetrahydrofuran to thefiltrate, the organic layer was separated out, washed with an aqueoussolution of sodium chloride and then dried over anhydrous magnesiumsulfate, followed by evaporation to recover the same product (0.9 g).Total yield: 4.5 g.

I.R. (Nujol): 3250, 1760, 1700, 1650, 1610, 1600 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 2.88 (3H, s), 3.75 (2H, q, J=17 Hz), 5.20 (1H, d,J=5 Hz), 5.23 (1H, d, J=11 Hz), 5.62 (1H, d, J=17 Hz), 5.77 (1H, dd, J=5Hz, 8 Hz), 6.51 (1H, s), 6.74 (1H, dd, J=11 Hz, 17 Hz), 6.94 (1H, s),7.10-7.54 (10H, m), 9.22 (1H, d, J=8 Hz).

EXAMPLE 52

Benzhydryl7-[2-(2-formamidothiazol-5-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate(11.48 g), mp 173° C. (dec.) was obtained by reacting benzhydryl7-amino-3-vinyl-3cephem-4-carboxylate hydrochloride (10.3 g) with theactivated acid, which was prepared from2-(2-formamidothiazol-5-yl)acetic acid (5.4 g), N,N-dimethylformamide(2.56 g) and phosphorus oxychloride (5.34 g), in a conventional manneraccording to the similar manner to that of Example 51.

I.R. (Nujol): 3270, 1770, 1715, 1680 cm⁻¹

N.M.R. δppm (DMSO-d₆): 3.78 (2H, s), 3.79 (2H, q, J=18 Hz), 5.24 (1H, d,J=5 Hz), 5.3-6.0 (3H, m), 6.5-7.1 (1H, m), 6.97 (1H, s), 7.2-7.7 (11H,m), 8.46 (1H, s), 9.23 (1H, d, J=8 Hz).

EXAMPLE 53

The activated acid, which was prepared from2-tert-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)-aceticacid (syn isomer) (13.8 g), N,N-dimethylformamide (3.66 g) andphosphorus oxychloride (7.7 g) in tetrahydrofuran (80 ml) in aconventional manner, was added to a solution of benzhydryl7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (15 g) andtrimethylsilylacetamide (32 g) in ethyl acetate (150 ml) at -20° C. withstirring, and the stirring was continued at the same temperature forhalf an hour. After addition of water (100 ml), the ethyl acetate layerwas separated out, and washed with an aqueous solution of sodiumchloride, an aqueous solution of sodium bicarbonate and then an aqueoussolution of sodium chloride in turn, followed by drying over anhydrousmagnesium sulfate. Removal of the solvent gave an oil, which waspulverized with diisopropyl ether and washed with the same to obtainbenzhydryl7-[2-tert-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (23.1 g), mp 101° C. (dec.).

I.R. (Nujol): 3250, 1780, 1720, 1680, 1540 cm⁻¹

N.M.R. δppm (DMSO-d₆): 1.45 (9H, s), 3.77 (2H, q, J=18 Hz), 4.64 (2H,s), 5.32 (1H, d, J=5 Hz), 5.2-6.0 (2H, m), 5.97 (1H, dd, J=5 Hz, 8 Hz),6.5-7.6 (1H, m), 6.98 (1H, s), 7.2-7.8 (11H, m), 8.55 (1H, s), 9.68 (1H,d, J=8 Hz), 12.71 (1H, broad s).

EXAMPLE 54

To a suspension of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylatehydrochloride (4.3 g) in methylene chloride (100 ml) was added2,6-lutidine (1.08 g) at 8° C., and the mixture was stirred for a while.To the resultant solution were added2-(2-methanesulfonamidothiazol-5-yl)acetic acid (2.6 ml) anddicyclohexylcarbodiimide (2.06 g) under ice-cooling with stirring, andthe stirring was continued at the same temperature for an hour and thenat ambient temperature for additional 3.5 hours. After addition ofwater, the precipitated substance was removed by filtration. Thefiltrate was washed with 10% hydrochloric acid, and the organic layerwas separated out, and washed with a saturated aqueous solution ofsodium bicarbonate and an aqueous solution of sodium chloride, followedby drying over anhydrous magnesium sulfate. Removal of the solvent gavea residue, which was washed with diethyl ether to obtain benzhydryl7-[2-(2-methanesulfonamidothiazol-5-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate(1.8 g). The same product (1.8 g) was recovered from the removedsubstance obtained above. Total yield: 3.6 g.

I.R. Nujol: 3320, 1770, 1710, 1660, 1620, 1570, 1520 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 2.90 (3H, s), 3.67 (2H, m), 5.22 (1H, d, J=5 Hz),5.30 (1H, d, J=11 Hz), 5.62 (1H, d, J=17 Hz), 5.77 (1H, dd, J=5 Hz, 8Hz), 6.75 (1H, dd, J=11 Hz, 17 Hz), 6.95 (1H, s), 7.03 (1H, s),7.17-7.60 (10H, m), 9.15 (1H, dd, J=5 Hz, 8 Hz).

The following compounds were obtained by reacting 7-amino-3-vinylcephalosporanic acid derivatives with the corresponding acids accordingto the similar manner to that of Example 53.

EXAMPLE 55

7-[2-(2-Aminothiazol-5-yl)acetamido]-3-vinyl-3-cephem-4-carboxylic acid.

I.R. (Nujol): 3550, 3280, 1725, 1650, 1540 cm⁻¹

EXAMPLE 56

Hexanoyloxymethyl7-[2-(2-aminothiazol-4-yl)-acetamido]-3-vinyl-3-cephem-4-carboxylate.

I.R. (Nujol): 3250, 1765, 1655 cm⁻¹.

EXAMPLE 57

Phthalid-3-yl7-[2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate.

I.R. (Nujol): 3250, 1780, 1760, 1650 cm⁻¹.

EXAMPLE 58

7-[2-(2-Guanidinothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylicacid hydrobromide.

I.R. (Nujol): 3400-3100, 1760, 1680, 1660, 1620, 1540 cm⁻¹.

EXAMPLE 59

Phthalid-3-yl7-[(2-aminothiazol-4-yl)glyoxylamido]-3-vinyl-3-cephem-4-carboxylate.

I.R. (Nujol): 3300, 1770, 1650 cm⁻¹.

EXAMPLE 60

Pivaloyloxymethyl7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

I.R. (Nujol): 3400-3100, 1770, 1745, 1670, 1610, 1530 cm⁻¹.

EXAMPLE 61

Phthalid-3-yl7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

I.R. (Nujol): 3300, 1775, 1670, 1610, 1530 cm⁻¹.

EXAMPLE 62

Benzhydryl7-[2-(2-aminothiazol-4-yl)-2-tert-butoxy-carbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

I.R. (Nujol): 3440, 3260, 3100, 1780, 1720, 1660, 1530 cm⁻¹.

EXAMPLE 63

A mixture of7-[2-(2-formamidothiazol-5-yl)-acetamido]-3-vinyl-3-cephem-4-carboxylicacid (4.67 g) and conc. hydrochloric acid (4.67 g) in methanol (93 ml)and tetrahydrofuran (46 ml) was stirred at 30° C. for 4 hours. After theorganic solvent was removed by evaporation, to the residue was addedwater (70 ml), followed by adjusting to pH 6 to 7 with 10% aqueoussolution of sodium hydroxide. After the insoluble substance was removedby filtration, the filtrate was adjusted to pH 3.0 with 10% hydrochloricacid under cooling, followed by stirring at the same temperature for 20minutes. The precipitated substance was collected by filtration, washedwith water and dried to give a residue, which was dissolved in anaqueous solution of sodium bicarbonate and then chromatographed onalumina (12 ml) using 5% aqueous sodium acetate as an eluent. Thefractions containing the desired compound were collected and acidifiedto pH 3.1 with 10% hydrochloric acid, and the precipitated substance wascollected by filtration and then dried to give7-[2-(2-aminothiazol-5-yl)acetamido]-3-vinyl-3-cephem-4-carboxylic acid(1.52 g), mp >290° C .

I.R. (Nujol): 3550, 3280, 1725, 1650, 1540 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.53 (2H, s), 3.70 (2H, q, J=18 Hz), 5.12 (1H, d,J=5 Hz), 5.2-5.8 (2H, m), 5.67 (1H, dd, J=5 Hz, 8 Hz), 6.73 (1H, s),6.7-7.4 (1H, m), 9.07 (1H, d, J=8 Hz).

EXAMPLE 64

A mixture of benzhydryl7-[2-tert-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (19.0 g) and conc. hydrochloric acid (11.6 g) in methanol(380 ml) was stirred at ambient temperature for 15 minutes. Afteraddition of water (200 ml), the reaction mixture was neutralized withsodium bicarbonate, followed by removing the methanol under reducedpressure. The resultant aqueous solution was extracted three times withethyl acetate, and the combined extract was washed with water and anaqueous solution of sodium chloride, and then dried over anhydrousmagnesium sulfate. Removal of the solvent gave an oil, which waspulverized with diisopropyl ether to obtain benzhydryl7-[2-(2-aminothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (15.3 g).

I.R. (Nujol): 3440, 3260, 3100, 1780, 1720, 1660, 1530 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.44 (9H, s), 3.77 (2H, q, J=18 Hz), 4.58 (2H,s), 5.29 (1H, d, J=5 Hz), 5.1-5.9 (2H, m), 5.90 (1H, dd, J=5 Hz, 8 Hz),6.5-7.8 (13H, m), 6.83 (1H, s), 6.93 (1H, s), 9.56 (1H, d, J=8 Hz).

The following compounds were obtained by reacting 7-acylamino-3-vinylcephalosporanic acid derivatives having a formamido group withhydrochloric acid according to the similar manner to that of Example 64.

EXAMPLE 65

Hexanoyloxymethyl7-[2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate.

I.R. (Nujol): 3250, 1765, 1655 cm⁻¹.

EXAMPLE 66

Phthalid-3-yl7-[2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate.

I.R. (Nujol): 3250, 1780, 1760, 1650 cm⁻¹.

EXAMPLE 67

Phthalid-3-yl7-[(2-aminothiazol-4-yl)glyoxylamido]-3-vinyl-3-cephem-4-carboxylate.

I.R. (Nujol): 3300, 1770, 1650 cm⁻¹.

EXAMPLE 68

Pivaloyloxymethyl7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

I.R. (Nujol): 3400-3100, 1770, 1745, 1670, 1610, 1530 cm⁻¹.

EXAMPLE 69

Phthalid-3-yl7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

I.R. (Nujol): 3300, 1775, 1670, 1610, 1530 cm⁻¹.

EXAMPLE 70

7-[2-(2-Aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. (Nujol): 3350, 1770, 1680, 1640 cm⁻¹.

EXAMPLE 71

Pivaloyloxymethyl7-[2-(2-aminothiazol-4-yl)-DL-glycolamido]-3-vinyl-3-cephem-4-carboxylate.

I.R. (Nujol): 3370, 1780, 1750, 1680, 1620 cm⁻¹.

EXAMPLE 72

Phthalid-3-yl7-[2-(2-aminothiazol-4-yl)-DL-glycolamido]-3-vinyl-3-cephem-4-carboxylate.

I.R. (Nujol): 1770, 1740, 1660, 1610 cm⁻¹.

EXAMPLE 73

To a suspension of benzhydryl7-[2-(2-methanesulfonamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate(4.5 g) in methylene chloride (30 ml) and anisole (4.6 g) was added2,2,2-trifluoroacetic acid (16.8 g) under ice-cooling, and the solutionwas stirred at ambient temperature for an hour. After evaporation of thereaction mixture, thereto were added water and ethyl acetate, followedby adjusting to pH 7 with 1N aqueous solution of sodium hydroxide. Tothe separated aqueous layer were added ethyl acetate andtetrahydrofuran, followed by adjusting to pH 2 with 10% hydrochloricacid. After the organic layer was separated out, it was washed with anaqueous solution of sodium chloride and then dried over anhydrousmagnesium sulfate. Removal of the solvent gave a residue, which waswashed with diethyl ether to obtain7-[2-(2-methanesulfonamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (1.5 g).

I.R. (Nujol): 3260, 3140, 3080, 1770, 1700, 1660, 1610, 1540 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 2.88 (3H, s), 3.55 (2H, s), 3.72 (2H, q, J=18Hz), 5.13 (1H, d, J=5 Hz), 5.30 (1H, d, J=11 Hz), 5.57 (1H, d, J=18 Hz),5.68 (1H, dd, J=5 Hz, 8 Hz), 6.50 (1H, s), 6.95 (1H, dd, J=11 Hz, 18Hz), 9.07 (1H, d, J=8 Hz).

EXAMPLE 74

7-[2-(2-Methanesulfonamidothiazol-5-yl)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (2.1 g) was obtained by reacting benzhydryl7-[2-(2-methanesulfonamidothiazol-5-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate(3.6 g) with 2,2,2-trifluoroacetic acid (13.2 g) in the presence ofanisole (3.7 g) according to the similar manner to that of Example 73.

I.R. (Nujol): 3250, 3110, 1770, 1705, 1660, 1560, 1530 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 2.88 (3H, s), 3.58 (2H, s), 3.68 (2H, q, J=18Hz), 5.13 (1H, d, J=5 Hz), 5.32 (1H, d, J=12 Hz), 5.56 (1H, d, J=18 Hz),5.68 (1H, dd, J=5 Hz, 8 Hz), 6.95 (1H, dd, J=12 Hz, 18 Hz), 7.07 (1H,s), 9.20 (1H, d, J=8 Hz).

The following compounds were obtained by reacting 7-acylamino-3-vinylcephalosporanic acid derivatives having benzhydryl ester with2,2,2-trifluoroacetic acid in the presence of anisole according to thesimilar manner to that of Example 73.

EXAMPLE 75

7-[2-(2-Aminothiazol-5-yl)acetamido]-3-vinyl-3-cephem-4-carboxylic acid.

I.R. (Nujol): 3550, 3280, 1725, 1650, 1540 cm⁻¹.

EXAMPLE 76

7-[2-(2-Guanidinothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylicacid hydrobromide.

I.R. (Nujol): 3400-3100, 1760, 1680, 1660, 1620, 1540 cm⁻¹.

EXAMPLE 77

To a suspension of benzhydryl7-[2-(2-formamidothiazol-5-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate(11.48 g) in methylene chloride (57.4 ml) and anisole (15 ml) was added2,2,2-trifluoroacetic acid (46 ml) under ice-cooling, and the mixturewas stirred at 7° to 8° C. for 15 minutes. After the reaction mixturewas poured into diisopropyl ether (600 ml), it was stirred underice-cooling for 20 minutes, followed by collecting the insolublesubstance by filtration and washing it with diisopropyl ether. Thissubstance (11.4 g) was suspended in water (150 ml), adjusted to pH 6.5with sodium bicarbonate and then treated with charcoal. The resultantfiltrate was adjusted to pH 2.0 with 10% hydrochloric acid, and theprecipitated substance was collected by filtration, washed with waterand then dried to give7-[2-(2-formamidothiazol-5-yl)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (5.88 g), mp 200° C. (dec.).

I.R. (Nujol): 3260, 3220, 3050, 1780, 1750, 1670, 1540 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.71 (2H, q, J=18 Hz), 3.76 (2H, s), 5.15 (1H, d,J=5 Hz), 5.3-6.9 (3H, m), 6.6-7.2 (1H, m), 7.29 (1H, s), 8.50 (1H, s),9.24 (1H, d, J=8 Hz).

EXAMPLE 78

(1) To a suspension of7-[2-(2-aminothiazol-4-yl)-DL-glycolamido]-3-vinyl-3-cephem-4-carboxylicacid (6.2 g) in water (60 ml) was added sodium bicarbonate (1.36 g) withstirring, and the stirring was continued for a while. The resultantsolution was lyophilized to prepare sodium 7-[2-(2-aminothiazol-4-yl)-DL-glycolamido]-3-vinyl-3-cephem-4-carboxylate (6.50 g).

(2) Thus prepared product (9.5 g) was suspended in N,N-dimethylformamide(95.0 ml), and the suspension was stirred under ice-cooling in a streamof nitrogen gas for 5 minutes. To the resultant solution was addeddropwise a solution of iodomethyl pivalate (5.7 g) inN,N-dimethylformamide (10 ml) under ice-cooling, and the mixture wasstirred at the same temperature for 10 minutes. After the reactionmixture was poured into a mixture of water and ethyl acetate, it wasstirred for a while. The organic layer was separated out and theremained aqueous solution was further extracted with ethyl acetate. Thisextract and the organic layer obtained above were combined, washed threetimes, with a saturated aqueous solution of sodium chloride, dried overanhydrous magnesium sulfate and then evaporated. To the residue wasadded diisopropyl ether, and the suspension was stirred for a while. Theinsoluble substance was collected by decantation and this operation wasrepeated three times to obtain pivaloyloxymethyl7-[2-(2-aminothiazol-4-yl)-DL-glycolamido]-3-vinyl-3-cephem-4-carboxylate(8.8 g), mp 90°-94° C.

    ______________________________________                                        I.R. (Nujol): 3370, 1780, 1750, 1680, 1620 cm.sup.-1                          N.M.R. δ ppm (DMSO-d.sub.6): 1.18 (9 H, m), 3.77 (2 H,                  q, J = 18.0 Hz), 4.90 (1 H, m), 5.19                                          (1 H, d, J = 5.0 Hz), 5.36 (1 H, d, J = 12.0 Hz),                             5.50-6.22 (4 H, m), 6.43 (1 H, s), 6.84                                       (1 H, dd, J = 12.0 Hz, 18.0 Hz),                                              8.36 (d, J = 8.0 Hz)                                                            (1 H)                                                                       8.47 (d, J = 8.0 Hz)                                                          ______________________________________                                    

EXAMPLE 79

Sodium7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (2.9 g), which was prepared from7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid and sodium bicarbonate in substantially the same manner as that ofExample 78-(1), was dissolved in N,N-dimethylformamide (30 ml), andthereto was added dropwise a solution of iodomethyl pivalate (1.62 g) inN,N-dimethylformamide (5 ml) under ice-cooling with stirring, and thestirring was continued at the same temperature for 10 minutes. To thereaction mixture were added ethyl acetate (200 ml) and water (150 ml),followed by separating out the organic layer, which was washed with asaturated aqueous solution of sodium bicarbonate and an aqueous solutionof sodium chloride, and then dried over anhydrous magnesium sulfate.Removal of the solvent gave an oil, which was pulverized withdiisopropyl ether to obtain pivaloyloxymethyl7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (2.1 g).

I.R. (Nujol): 3400-3100, 1770, 1745, 1670, 1610, 1530 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.18 (9H, s), 3.77 (2H, q, J=18 Hz), 3.84 (3H,s), 5.23 (1H, d, J=5 Hz), 5.38 (1H, d, J=11 Hz), 5.69 (1H, d, J=18 Hz),5.64-6.00 (3H, m), 6.75 (1H, s), 6.82 (1H, dd, J=11 Hz, 18 Hz), 7.24(2H, broad s), 9.60 (1H, d, J=8 Hz).

EXAMPLE 80

To a solution of sodium7-[2-(2-aminothiazol-4-yl)-acetamido]-3-vinyl-3-cephem-4-carboxylate(2.0 g) in N,N-dimethylformamide (20 ml) were added iodomethyl hexanoate(3.4 g) and sodium iodide (3.1 g) in a stream of nitrogen, and themixture was stirred at ambient temperature for 1.5 hours. After thereaction mixture was poured into a mixture of ethyl acetate (200 ml) andwater (200 ml), the organic layer was separated out, washed with waterand a saturated aqueous solution of sodium chloride, and then dried overanhydrous magnesium sulfate, followed by treating with charcoal. Thefiltrate was concentrated, and thereto was added diisopropyl ether,followed by collecting the precipitated substance by filtration toobtain hexanoyloxymethyl7-[2-(2-aminothiazol-4-yl)-acetamido]-3-vinyl-3-cephem-4-carboxylate(1.5 g).

I.R. (Nujol): 3250, 1765, 1655 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.2 (10H, m), 2.41 (2H, m), 3.40 (2H, s), 3.75(2H, q, J=16 Hz), 5.15 (1H, d, J=5 Hz), 5.58 (3H, m), 5.82 (2H, s), 6.23(1H, s), 6.72 (1H, dd, J=12 Hz, 18 Hz), 6.90 (2H, m), 8.87 (1H, d, J=8Hz).

EXAMPLE 81

To a solution of7-[(2-aminothiazol-4-yl)glyoxylamido]-3-vinyl-3-cephem-4-carboxylic acid(1.0 g) in N,N-dimethylformamide (10 ml) were added triethylamine (0.27g), 3-bromophthalide (0.56 g) and sodium iodide (0.39 g) at 10° C. withstirring, and the stirring was continued at the same temperature forhalf an hour. After the reaction mixture was poured into water (50 ml),it was extracted with a mixture of tetrahydrofuran and ethyl acetate(1:1 by volume). The extract was washed with a saturated aqueoussolution of sodium chloride and then dried over anhydrous magnesiumsulfate, followed by evaporation to give an oil, which was pulverizedwith diisopropyl ether to obtain phthalid-3-yl7-[(2-aminothiazol-4-yl)glyoxylamido]-3-vinyl-3-cephem-4-carboxylate(1.0 g).

I.R. (Nujol): 3300, 1770, 1650 cm⁻¹.

EXAMPLE 82

To a solution of sodium7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (2.16 g) in N,N-dimethylformamide (20 ml) were added3-bromophthalide (1.3 g) and sodium iodide (1.35 g), and the mixture wasstirred at ambient temperature for 40 minutes. Thereto were added ethylacetate (100 ml) and water (50 ml), and the separated ethyl acetatelayer was washed with a saturated aqueous solution of sodium bicarbonateand an aqueous solution of sodium chloride, and then dried overanhydrous magnesium sulfate. After removal of the solvent, the residue(2.6 g) was chromatographed on silica gel (50 g) using a mixture ofbenzene and ethyl acetate as an eluent. The fractions containing thedesired compound were collected and evaporated to give phthalid-3-yl7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (1.4 g).

    ______________________________________                                        I.R. (Nujol):                                                                 3300, 1775, 1670, 1610, 1530 cm.sup.-1                                        N.M.R. δ ppm (DMSO-d.sub.6):                                            3.80 (2 H, m), 3.88 (3 H, s),                                                 5.23 (1 H, d, J = 4 Hz), 5.20-6.00 (3 H, m),                                  6.78 (s)                                                                       (1 H), 7.05 (1 H, dd, J = 11 Hz, 17 Hz),                                     6.82 (s)                                                                      7.65 (s)                                                                       (1 H), 7.67-8.10 (4 H, m),                                                   7.68 (s)                                                                      9.67 (d, J = 8 Hz)                                                             (1 H)                                                                        9.70 (d, J = 8 Hz)                                                            ______________________________________                                    

EXAMPLE 83

To a solution of7-[2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylic acid(2.0 g) in N,N-dimethylformamide (15 ml) were added triethylamine (0.55g), 3-bromophthalide (1.2 g) and sodium iodide (0.82 g) in turn in astream of nitrogen, and the mixture was stirred at ambient temperaturefor half an hour. After the reaction mixture was poured into a mixtureof ethyl acetate (300 ml) and water (200 ml), the organic layer wasseparated out, washed with water and a saturated aqueous solution ofsodium chloride, and then dried over anhydrous magnesium sulfate,followed by treating with charcoal. After the filtrate was concentratedand thereto was added diethyl ether. The precipitated substance wascollected by filtration to obtain phthalid-3-yl7-[2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (1.5g).

    ______________________________________                                        I.R. (Nujol):                                                                 3250, 1780, 1760, 1650 cm.sup.-1                                              N.M.R. δ ppm (DMSO-d.sub.6):                                            3.43 (2 H, s), 3.80 (2 H, m),                                                 5.15 (1 H, d, J = 5 Hz), 5.6 (3 H, m), 6.23                                   (1 H, s), 6.87 (2 H, m), 7.03 (1 H, dd,                                       J = 12 Hz, 18 Hz), 7.60 (s)                                                    (1 H),                                                                       7.63 (s)                                                                      7.8 (4 H, m), 8.83 (d, J = 8 Hz)                                               (1 H)                                                                        8.86 (d, J = 8 Hz)                                                            ______________________________________                                    

EXAMPLE 84

Phthalid-3-yl7-[2-(2-aminothiazol-4-yl)-DL-glycolamido]-3-vinyl-3-cephem-4-carboxylatewas obtained according to the similar manner to that of Example 83.

I.R. (Nujol): 1770, 1740, 1660, 1610 cm⁻¹.

EXAMPLE 85

To a solution of phthalid-3-yl7-[(2-aminothiazol-4-yl)glyoxylamido]-3-vinyl-3-cephem-4-carboxylate(0.3 g) in methanol (9.0 ml) and tetrahydrofuran (3.0 ml) was addedsodium borohydride (0.012 g) under ice-cooling, and the mixture wasstirred at the same temperature for 30 minutes. After removal of thesolvent, the residue was dissolved in a mixture of water (15 ml),tetrahydrofuran (15 ml) and ethyl acetate (15 ml), followed by adjustingto pH 7.0 with 10% hydrochloric acid. The separated organic layer waswashed twice with a saturated aqueous solution of sodium chloride andthen dried over anhydrous magnesium sulfate. After removal of thesolvent, the residue was chromatographed on silica gel using a mixtureof ethyl acetate and chloroform (17:3 by volume) as an eluent. Thefractions containing the desired compound were collected and evaporatedto dryness to give a residue, which was pulverized with diisopropylether and washed with the same to obtain phthalid-3-yl7-[2-(2-aminothiazol-4-yl)-DL-glycolamido]-3-vinyl-3-cephem-4-carboxylate(0.14 g), mp 118°-120° C. (dec.).

I.R. (Nujol): 1770, 1740, 1660, 1610 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.80 (2H, m), 4.84 (1H, m), 5.14 (1H, d, J=4.0Hz), 5.19-6.04 (3H, m), 6.38 (1H, s), 6.93 (1H, m), 7.54-8.04 (5H, m),8.33 (1H, m).

EXAMPLE 86

Pivaloyloxymethyl7-[2-(2-aminothiazol-4-yl)-DL-glycolamido]-3-vinyl-3-cephem-4-carboxylatewas obtained according to the similar manner to that of Example 85.

I.R. (Nujol): 3370, 1780, 1750, 1680, 1620 cm⁻¹.

EXAMPLE 87

A suspension of 7-amino-3-vinyl-3-cephem-4-carboxylic acid (1.95 g) andtrimethylsilylacetamide (5.6 g) in ethyl acetate (20 ml) was stirred at40° C. for a while to prepare the solution A.

On the other hand, to a solution of diketene (0.87 g) in carbontetrachloride (9 ml) was added dropwise a solution of bromine (1.65 g)in carbon tetrachloride (2 ml) at -20° C., and the mixture was stirredat -10° C. for half an hour to prepare the solution B.

To the solution A was added the solution B at -20° to -10° C., and themixture was stirred at the same temperature for half an hour. Afterethyl acetate (80 ml) and water (80 ml) were added to the reactionmixture, the organic layer was separated out, washed with an aqueoussolution of sodium chloride, and then dried over anhydrous magnesiumsulfate, followed by evaporation under reduced pressure to give7-(4-bromo-3-oxo-butyramido)-3-vinyl-3-cephem-4-carboxylic acid (3.2 g).This product was dissolved in a mixture of tetrahydrofuran (50 ml) andethanol (50 ml), and thereto was added 1-amidinothiourea (1.7 g),followed by stirring for 2 hours. The precipitated substance wascollected by filtration and then dried to give7-[2-(2-guanidinothiazol-4-yl)-acetamido]-3-vinyl-3-cephem-4-carboxylicacid hydrobromide (0.7 g).

I.R. (Nujol): 3400-3100, 1760, 1680, 1660, 1620, 1540 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.27-3.95 (4H, m), 5.1-5.91 (4H, m), 6.9 (1H, s),7.1 (1H, dd, J=11 Hz, 17 Hz), 9.1 (1H, d, J=8 Hz).

The following compounds were obtained by reacting 7-amino-3-vinylcephalosporanic acid derivatives with diketene, bromine and thioureaaccording to the similar manner to that of Example 87.

EXAMPLE 88

Hexanoyloxymethyl7-[2-(2-aminothiazol-4-yl)-acetamido]-3-vinyl-3-cephem-4-carboxylate.

I.R. (Nujol): 3250, 1765, 1655 cm⁻¹.

EXAMPLE 89

Phthalid-3-yl7-[2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate.

I.R. (Nujol): 3250, 1780, 1760, 1650 cm⁻¹.

EXAMPLE 90

To a suspension of benzhydryl7-[2-(2-aminothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (15.0 g) in anisole (15 ml) was added 2,2,2-trifluoroaceticacid (60 ml) under ice-cooling with stirring, and the stirring wascontinued at 10° to 15° C. for 80 minutes. After the reaction mixturewas poured into diisopropyl ether (600 ml), the insoluble substance wascollected by filtration and then dried. This substance (11.2 g) wasdissolved in an aqueous solution of sodium bicarbonate so as to adjustthe resultant solution to pH 6.0, and then chromatographed on alumina(44.8 ml) using 5% aqueous sodium acetate as an eluent. The fractionscontaining the desired compound were collected and evaporated to drynessto give7-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (3.55 g), mp>250° C.

I.R. (Nujol): 3350, 1770, 1680, 1640 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.70 (2H, q, J=18 Hz), 4.62 (2H, s), 5.21 (1H, d,J=5 Hz), 5.82 (1H, dd, J=5 Hz, 8 Hz), 5-6 (2H, m), 6.82 (1H, s), 7.22(2H, broad s), 6.5-7.5 (1H, m), 9.50 (1H, d, J=8 Hz).

EXAMPLE 91

A mixture of benzhydryl7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-triphenylphosphoranylidenemethyl-3-cephem-4-carboxylate(syn isomer) (2.2 g), 36% aqueous formaldehyde (20 ml) andtetrahydrofuran (60 ml) were stirred at ambient temperature for 12.5hours. After addition of ethyl acetate (100 ml) to the reaction mixture,the organic layer was separated out, washed with 10% hydrochloric acidand an aqueous solution of sodium chloride, and then dried overanhydrous magnesium sulfate. Removal of the solvent gave a residue,which was pulverized with diethyl ether, and chromatographed on silicagel using chloroform and then a mixture of chloroform and acetone (19:1and 9:1 by volume) as an eluent. The fractions containing the desiredcompound were collected and evaporated to give benzhydryl7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (0.25 g).

I.R. (Nujol): 3250, 1780, 1710, 1700, 1660, 1540 cm⁻¹.

EXAMPLE 92

[4-Benzhydryloxycarbonyl-7-{2-tert-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido}-3-cephem-3-yl]methyltriphenyl-phosphoniumiodide (syn isomer) (0.59 g) was dissolved in a mixture of methylenechloride (20 ml), water (10 ml) and 36% aqueous formaldehyde (1 ml),followed by adjusting to pH 8.0 with 20% aqueous sodium carbonate. Afterstirring for 3 hours at 30°-35° C., the reaction mixture was furtheradjusted to pH 2.0 with 10% hydrochloric acid and then extracted withmethylene chloride. The extract was washed with an aqueous sodiumchloride dried over magnesium sulfate and then evaporated. The residue(0.46 g) was chromatographed on silica gel using a mixed solvent ofbenzene and ethyl acetate (2:1 by volume) as an eluent to obtainbenzhydryl7-[2-tert-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (0.14 g).

I.R. (Nujol): 3250, 1780, 1720, 1680, 1540 cm⁻¹.

The following compounds were obtained by reacting7-acylamino-3-triphenylphosphoranylidenemethylcephalosporanic acidderivative with an aqueous formaldehyde according to the similar mannerto that of Examples 91 and 92.

EXAMPLE 93

Benzhydryl7-[2-(2-methanesulfonamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate.

I.R. (Nujol): 3250, 1760, 1700, 1650, 1610, 1600 cm⁻¹.

EXAMPLE 94

Benzhydryl7-[2-(2-formamidothiazol-5-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate.

I.R. (Nujol): 3270, 1770, 1715, 1680 cm⁻¹.

EXAMPLE 95

Benzhydryl7-[2-(2-methanesulfonamidothiazol-5-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate.

I.R. (Nujol): 3320, 1770, 1710, 1660, 1620, 1570, 1520 cm⁻¹.

EXAMPLE 96

Pivaloyloxymethyl7-[2-(2-aminothiazol-4-yl)-DL-glycolamido]-3-vinyl-3-cephem-4-carboxylate.

I.R. (Nujol): 3370, 1780, 1750, 1680, 1620 cm⁻¹.

EXAMPLE 97

Pivaloyloxymethyl7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

I.R. (Nujol): 3400-3100, 1770, 1745, 1670, 1610, 1530 cm⁻¹.

EXAMPLE 98

Hexanoyloxymethyl7-[2-(2-aminothiazol-4-yl)-acetamido]-3-vinyl-3-cephem-4-carboxylate.

I.R. (Nujol): 3250, 1765, 1655 cm⁻¹.

EXAMPLE 99

Phthalid-3-yl7-[(2-aminothiazol-4-yl)glyoxylamido]-3-vinyl-3-cephem-4-carboxylate.

I.R. (Nujol): 3300, 1770, 1650 cm⁻¹.

EXAMPLE 100

Phthalid-3-yl7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

I.R. (Nujol): 3300, 1775, 1670, 1610, 1530 cm⁻¹.

EXAMPLE 101

Phthalid-3-yl7-[2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate.

I.R. (Nujol): 3250, 1780, 1760, 1650 cm⁻¹.

EXAMPLE 102

Phthalid-3-yl7-[2-(2-aminothiazol-4-yl)-DL-glycolamido]-3-vinyl-3-cephem-4-carboxylate.

I.R. (Nujol): 1770, 1740, 1660, 1610 cm⁻¹.

EXAMPLE 103

To a solution of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate (3.02g) in methylene chloride (30 ml) were added a solution of2-(2-formamidothiazol-4-yl)-2-(L-2-benzhydryloxycarbonyl-2-tert-butoxycarbonylaminoethoxycarbonylmethoxyimino)aceticacid (syn isomer) (5.5 g) and then N,N'-dicyclohexylcarbodiimide (1.81g), followed by stirring at ambient temperature for 2 hours. Diethylether (100 ml) was added to the reaction mixture, and the precipitatedmaterial was removed by filtration. After removing the solvent from thefiltrate, the residue was dissolved in ethyl acetate, washed with 5%aqueous sodium bicarbonate and then an aqueous sodium chloride, followedby drying over anhydrous magnesium sulfate. Removal of the solvent gavea residue (10 g), which was chromatographed on silica gel (200 ml)eluting with a mixed solvent of diisopropyl ether and acetone. Fractionscontaining a desired compound were collected and evaporated to obtainbenzhydryl7-[2-(2-formamidothiazol-4-yl)-2-(L-2-benzhydryloxycarbonyl-2-tert-butyoxycarbonylaminoethoxycarbonylmethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (5.9 g), mp 87° -94° C.

IR (Nujol): 3350, 1780, 1720, 1700 (broad) cm⁻¹.

NMR δppm (DMSO-d₆): 1.33 (9H, s), 3.57, 3.96 (2H, ABq, J=18 Hz), 4.53(3H, m), 4.73 (2H, broad s), 5.3 (1H, d, J=11 Hz), 5.33 (1H, d, J=5 Hz),5.53 (1H, d, J=18 Hz), 6.00 (1H, dd, J=5 Hz, 8 Hz), 6.87 (1H, s), 7.00(1H, s), 7.4 (20H, m), 7.50 (1H, s), 8.57 (1H, s), 9.80 (1H, d, J=8 Hz),12.7 (1H, broad s).

EXAMPLE 104

To a solution of benzyhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate(3.54 g) in methylene chloride (35 ml) were added a solution of2-(2-formamidothiazol-4-yl)-2-(DL-3-benzhydryloxycarbonyl-3-tert-butoxycarbonylaminopropoxyimino)aceticacid (syn isomer) (6.0 g) in tetrahydrofuran (60 ml) and thenN,N'-dicyclohexylcarbodiimide (2.2 g), followed by stirring at ambienttemperature for 4 hours. The precipitated material was removed byfiltration, and the filtrate was evaporated to dryness to give aresidue, which was chromatographed on silica gel eluting with a mixedsolvent of diisopropyl ether and acetone. Fractions containing a desiredcompound were collected and evaporated to obtain benzhydryl7-[2-(2-formamidothiazol-4-yl)-2-(DL-3-benzhydryloxycarbonyl-3-tert-butoxycarbonylaminopropoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (3.80 g), mp 153°-158° C.

IR (Nujol): 3200, 1780, 1700 (broad) cm⁻¹.

NMR δppm (DMSO-d₆): 1.36 (9H, s), 2.1 (2H, m), 3.6 (2H, m), 4.2 (3H, m),5.2-6.1 (4H, m), 6.8 (1H, s), 6.97 (1H, s), 6.8-7.2 (1H, m), 7.37 (20H,m), 7.43 (1H, s), 8.53 (1H, s), 9.75 (1H, d, J=8 Hz), 12.7 (1H, broads).

EXAMPLE 105

To a solution of N,N-dimethylformamide (1.10 ml) and tetrahydrofuran (6ml) was added dropwise phosphorus oxychloride (1.30 ml), followed bystirring for 10 minutes. After addition of tetrahydrofuran (25 ml) and2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer) (2.96g), the mixture was stirred at 5° C. for 45 minutes to prepare theactivated acid solution. This solution was added dropwise to a solutionof L-2-benzhydryloxycarbonyl-2-tert-butoxycarbonylaminoethyl7-amino-3-vinyl-3-cephem-4-carboxylate (5.0 g) andtrimethylsilylacetamide (9.05 g) in methylene chloride (50 ml) at -30°C. in the course of 5 minutes, followed by stirring at -20° to -10° C.for half an hour. The reaction mixture was poured into a mixture ofethyl acetate (300 ml) and water (100 ml), and then adjusted to pH 7.5with 10% aqueous sodium hydroxide and an aqueous sodium bicarbonate. Theseparated ethyl acetate solution was washed with an aqueous sodiumchloride and then dried over anhydrous magnesium sulfate. Removal of thesolvent gave crude product (7.5 g) ofL-2-benzhydryloxycarbonyl-2-tert-butoxycarbonylaminoethyl7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(sym isomer).

IR (Nujol): 3280, 1782, 1709, 1689, 1656 cm⁻¹.

NMR δppm (DMSO-d₆): 1.40 (9H, s), 3.73 (2H, m), 3.92 (3H, s), 4.56 (3H,m), 5.20 (1H, d, J=5 Hz), 5.33 (1H, d, J=11 Hz), 5.65 (1H, d, J=18 Hz),5.75 (1H, dd, J=5 Hz, 8 Hz), 6.84 (1H, s), 6.93 (1H, dd, J=11 Hz, 18Hz), 7.37 (10H, m), 7.43 (1H, s), 8.53 (1H, s), 9.73 (1H, d, J=8 Hz),12.7 (1H, broad s).

EXAMPLE 106

To a Vilsmeier reagent, which was prepared by N,N-dimethylformamide(1.44 ml) and phosphorus oxychloride (1.71 ml) in tetrahydrofuran (6 ml)in a conventional manner, was added (2-formamidothiazol-4-yl)glyoxylicacid (3.108 g), followed by stirring for a while. Thereto were addedN,N-dimethylformamide (45 ml) and tetrahydrofuran (60 ml) to prepare theactivated acid solution. This activated acid solution was added dropwiseto a solution ofL-2-benzhydryloxycarbonyl-2-tert-butoxycarbonylaminoethyl7-amino-3-vinyl-3-cephem-4-carboxylate (4.5 g) andtrimethylsilylacetamide (8.4 g) in methylene chloride (45 ml) at -30° C.in the course of 5 minutes. To the reaction mixture was added ethylacetate (400 ml), followed by adjusting to pH 7.5 with an aqueous sodiumbicarbonate. After washing with an aqueous sodium chloride, the solutionwas dried over anhydrous magnesium sulfate. Removal of the solvent gavecrude product (8.0 g) ofL-2-benzhydryloxycarbonyl-2-tert-butoxycarbonylaminoethyl-7-[(2-formamidothiazol-4-yl)glyoxylamido]-3-vinyl-3-cephem-4-carboxylate.

IR (Nujol): 1777, 1720, 1667 cm⁻¹.

NMR δppm (DMSO-d₆): 1.37 (9H, s), 3.67 (2H, m), 4.43 (3H, broad s), 5.10(1H, d, J=5 Hz), 5.20 (1H, d, J=11 Hz), 5.55 (1H, d, J=18 Hz), 5.58 (1H,dd, J=5 Hz, 8 Hz), 6.71 (1H, s), 7.23 (10H, m), 8.37 (1H, s), 8.47 (1H,s), 9.77 (1H, d, J=8 Hz), 12.7 (1H, broad s).

EXAMPLE 107

Benzhydryl7-[2-(2-formamidothiazol-5-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (2.9 g), mp 208° C. (dec.), was obtained by reactingbenzhydryl 7-amino-3-cephem-4-carboxylate hydrochloride (2.28 g) with2-(2-formamidothiazol-5-yl)-2-methoxyiminoacetic acid (syn isomer) (1.4g) according to a similar manner to those of Examples 105 and 106.

IR (Nujol): 3250, 1780, 1720, 1685, 1655, 1570 cm⁻¹.

NMR δppm (DMSO-d₆): 3.82 (2H, q, J=18 Hz), 3.92 (3H, s), 5.30 (1H, d,J=11 Hz), 5.32 (1H, d, J=5 Hz), 5.67 (1H, d, J=17 Hz), 5.92 (1H, dd,J=5.8 Hz), 6.85 (1H, dd, J=11 Hz, 17 Hz), 7.00 (1H, s), 7.2-7.6 (10H,m), 7.61 (1H, s), 8.62 (1H, s), 9.98 (1H, d, J=8 Hz).

EXAMPLE 108

Benzhydryl7-[2-(2-formamidothiazol-5-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(anti isomer) (4.14 g) was obtained by reacting benzhydryl7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (3.26 g) with2-(2-formamidothiazol-5-yl)-2-methoxyiminoacetic acid (anti isomer) (2.0g) according to a similar manner to those of Examples 105 and 106.

IR (Nujol): 3250, 1780, 1720, 1685, 1660 cm⁻¹.

NMR δppm (DMSO-d₆): 3.79 (2H, q, J=18 Hz), 4.12 (3H, s), 5.34 (1H, d,J=5 Hz), 5.31 (1H, d, J=11 Hz), 5.65 (1H, d, J=18 Hz), 5.83 (1H, dd, J=5Hz, 8 Hz), 6.83 (1H, dd, J=11 Hz, 18 Hz), 7.00 (1H, s), 7.42 (10H, broads), 8.26 (1H, s), 8.62 (1H, s), 9.55 (1H, d, J=8 Hz).

EXAMPLE 109

Benzhydryl7-[(2-formamidothiazol-5-yl)glyoxylamido]-3-vinyl-3-cephem-4-carboxylate(3.0 g), mp 178° C. (dec.), was obtained by reacting benzhydryl7-amino-3-vinyl3-cephem-4-carboxylate hydrochloride (2.68 g) with(2-formamidothiazol-5-yl)glyoxylic acid (1.5 g) according to a similarmanner to those of Examples 105 and 106.

IR (Nujol): 3280, 1775, 1730, 1705, 1635, 1555 cm⁻¹.

NMR δppm (DMSO-d₆): 3.80 (2H, q, J=17 Hz), 5.34 (1H, d, J=5 Hz), 5.35(1H, d, J=11 Hz), 5.70 (1H, d, J=17 Hz), 5.82 (1H, dd, J=5 Hz, 8 Hz),6.89 (1H, dd, J=11 Hz, 17 Hz), 7.2-7.8 (10H, m), 6.99 (1H, s), 8.58 (1H,s), 8.68 (1H, s), 9.92 (1H, d, J=8 Hz), 12.98 (1H, broad s).

EXAMPLE 110

Benzhydryl7-[2-(2-formamidothiazol-4-yl)-2-ethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (25.0 g) was obtained by reacting benzhydryl7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (17.2 g) with2-(2-formamidothiazol-4-yl)-2-ethoxyiminoacetic acid (syn isomer) (8.8g) according to a similar manner to those of Examples 105 and 106.

IR (Nujol): 3260, 3150, 1770, 1720, 1700, 1660, 1620, 1560, 1540 cm⁻¹.

NMR δppm (DMSO-d₆): 1.27 (3H, t, J=7 Hz), 3.79 (2H, q, J=17 Hz), 4.18(2H, q, J=7 Hz), 5.32 (1H, d, J=5 Hz), 5.33 (1H, d, J=11 Hz), 5.65 (1H,d, J=17 Hz), 5.96 (1H, dd, J=5 Hz, 8 Hz), 6.78 (1H, dd, J=11 Hz, 17 Hz),6.97 (1H, s), 7.17-7.67 (11H, m), 8.55 (1H, s), 9.73 (1H, d, J=8 Hz),12.70 (1H, broad s).

EXAMPLE 111

Benzhydryl7-[2-(2-formamidothiazol-4-yl)-2-hexyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (5.7 g) was obtained by reacting benzhydryl7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (4.29 g) with2-(2-formamidothiazol-4-yl)-2-hexyloxyiminoacetic acid (syn isomer)(3.29 g) according to a similar manner to those of Examples 105 and 106.

IR (Nujol): 3250, 1770, 1710, 1700, 1650, 1570, 1535 cm⁻¹.

NMR δppm (DMSO-d₆): 0.87 (3H, t, J=6 Hz), 1.0-2.0 (8H, m), 3.75 (2H,ABq, J=18 Hz), 4.12 (2H, t, J=6 Hz), 5.28 (1H, d, J=5 Hz), 5.42 (1H, d,J=11 Hz), 5.62 (1H, d, J=17 Hz), 5.90 (1H, dd, J=5 Hz, 8 Hz), 6.77 (1H,dd, J=11 Hz, 17 Hz), 6.97 (1H, s), 7.12-7.75 (11H, m), 8.50 (1H, s),9.52 (1H, d, J=8 Hz), 12.70 (1H, broad s).

The following compounds were obtained by reacting 7-amino-3-vinylcephalosporanic acid derivatives with hydrochloride of the correspondingacid according to a similar manner to those of Examples 105 and 106.

EXAMPLE 112

7-[2-(2-Aminothiazol-5-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer), mp >250° C.

IR (Nujol): 3300, 1780, 1645, 1580, 1515 cm⁻¹.

EXAMPLE 113

7-[2-(2-Aminothiazol-5-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (anti isomer), mp >250° C.

IR (Nujol): 3320, 1775, 1655, 1575, 1515 cm⁻¹.

EXAMPLE 114

7-[(2-Aminothiazol-5-yl)glyoxylamido]-3-vinyl-3-cephem-4-carboxylicacid, mp >250° C.

IR (Nujol): 3300, 3180, 1770, 1690, 1620, 1510, 1460 cm⁻¹.

EXAMPLE 115

7-[2-(2-Aminothiazol-4-yl)-2-ethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer)

IR (Nujol): 3300, 1770, 1660, 1545 cm⁻¹.

EXAMPLE 116

Pivaloyloxymethyl7-[2-(2-aminothiazol-4-yl)-2-pivaloyloxymethoxycarbonylmethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer), mp 115° C. (dec.).

IR (Nujol): 3400, 3260, 3100, 1780, 1750, 1660, 1530 cm⁻¹.

EXAMPLE 117

Pivaloyloxymethyl7-[2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3300, 1780, 1740, 1670, 1610, 1530 cm⁻¹.

EXAMPLE 118

7-[2-(2-Aminothiazol-4-yl)-2-hexyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer), mp 147°-155° C. (dec.).

IR (Nujol): 3250, 1770, 1660, 1530 cm⁻¹.

EXAMPLE 119

Acetoxymethyl7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer), mp 78°-83° C.

IR (Nujol): 3300, 1765 (broad), 1660, 1610, 1535 cm⁻¹.

EXAMPLE 120

Propionyloxymethyl7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer), mp 79°-85° C.

IR (Nujol): 3350, 1770 (broad), 1650, 1620, 1530 cm⁻¹.

EXAMPLE 121

Isobutyryloxymethyl7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer), mp 92°-100° C. (dec.).

IR (Nujol): 3400-3100, 1780-1740, 1670, 1610, 1530 cm⁻¹.

EXAMPLE 122 1-Acetoxypropyl7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer), mp 97°-101° C.

IR (Nujol): 3300, 1765, 1670, 1610 cm⁻¹.

EXAMPLE 123

L-2-Amino-2-carboxyethyl7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 3200, 1770, 1735 (shoulder), 1650 (broad) cm⁻¹.

EXAMPLE 124

L-2-Benzhydryloxycarbonyl-2-tert-butoxycarbonylaminoethyl7-[(2-aminothiazol-4-yl)glyoxylamido]-3-vinyl-3-cephem-4-carboxylate.

IR (Nujol): 3340, 1775, 1720, 1660, 1614 cm⁻¹.

EXAMPLE 125

Benzhydryl7-[2-(2-aminothiazol-4-yl)-2-(L-2-benzhydryloxycarbonyl-2-tert-butoxycarbonylaminoethoxycarbonylmethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer), mp 124°-128° C.

IR (Nujol): 3360, 1750 (broad) cm⁻¹.

EXAMPLE 126

Benzhydryl7-[2-(2-aminothiazol-4-yl)-2-(DL-3-benzhydryloxycarbonyl-3-tert-butoxycarbonylaminopropoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer), mp 119°-122° C.

IR (Nujol): 3300, 1780, 1719, 1680 cm⁻¹.

EXAMPLE 127

To a suspension of 2-(5-amino-1,2,4-oxadiazol-3-yl)-2-methoxyiminoaceticacid (syn isomer) (2.23 g) in methylene chloride (70 ml) was addedphosphorus oxychloride (7.2 g), followed by stirring at ambienttemperature for 45 minutes. Thereto was added N,N-dimethylformamide (4.4g) at -10° C., and the mixture was stirred at -10° to 0° C. for an hourto prepare the activated acid solution. This solution was added to asolution of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylatehydrochloride (4.7 g) and trimethylsilylacetamide (8.6 g) in ethylacetate (50 ml) at -20° C., and the mixture was stirred at -20° to 0° C.for an hour. After ethyl acetate (200 ml) and water (200 ml) were addedto the reaction mixture, the ethyl acetate layer was separated out,washed with a saturated aqueous sodium bicarbonate and an aqueous sodiumchloride, and then dried over anhydrous magnesium sulfate. Removal ofthe solvent gave a residue, which was chromatographed on silica geleluting with a mixed solvent of ethyl acetate and benzene (6:4 byvolume). Fractions containing a desired compound firstly eluted werecollected and evaporated to obtain benzhydryl7-[2-(5-amino-1,2,4-oxadiazol-3-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (2.4 g).

IR (Nujol): 3250, 1770, 1710, 1670, 1600, 1550 cm⁻¹.

NMR δppm (DMSO-d₆): 3.77 (2H, q, J=17 Hz), 3.97 (3H, s), 5.28 (1H, d,J=5 Hz), 5.28 (1H, d, J=11 Hz), 5.65 (1H, d, J=17 Hz), 5.92 (1H, dd, J=5Hz, 8 Hz), 6.78 (1H, dd, J=11 Hz, 17 Hz), 6.97 (1H, s), 7.17-7.67 (10H,m), 8.03 (2H, s), 9.77 (1H, d, J=8 Hz).

Fractions contaning another desired compound secondly eluted werecollected and evaporated to obtain benzhydryl7-[2-[5-{N-(N,N-dimethylaminomethylene)amino}-1,2,4-oxadiazol-3-yl]-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (2.0 g).

IR (Nujol): 3200, 1780, 1720, 1680, 1640, 1540 cm⁻¹.

NMR δppm (DMSO-d₆): 3.07 (3H, s), 3.22 (3H, s), 3.68 (2H, m), 4.00 (3H,s), 5.30 (1H, d, J=5 Hz), 5.32 (1H, d, J=11 Hz), 5.67 (1H, d, J=17 Hz),5.95 (1H, dd, J=5 Hz, 8 Hz), 6.80 (1H, dd, J=11 Hz, 17 Hz), 6.98 (1H,s), 7.20-7.67 (10H, m), 8.65 (1H, s), 9.83 (1H, d, J=8 Hz).

EXAMPLE 128

Benzhydryl7-[2-(5-amino-1,2,4-oxadiazol-3-yl)-acetamido]-3-vinyl-3-cephem-4-carboxylate(2.1 g) was obtained by reacting benzhydryl7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (4.3 g) with2-(5-amino-1,2,4-oxadiazol-3-yl)acetic acid (1.72 g) according to asimilar manner to that of Example 127.

IR (Nujol): 3380, 3250, 3180, 3130, 1770, 1710, 1650, 1540 cm⁻¹.

NMR δppm (DMSO-d₆): 3.35 (2H, s), 3.78 (2H, q, J=18 Hz), 5.23 (1H, d,J=5 Hz), 5.32 (1H, d, J=11 Hz), 5.65 (1H, d, J=17 Hz), 5.82 (1H, dd, J=5Hz, 8 Hz), 6.80 (1H, dd, J=11 Hz, 17 Hz), 7.00 (1H, s), 7.20-7.67 (10H,m), 7.73 (2H, s), 9.18 (1H, d, J=8 Hz).

EXAMPLE 129

To a solution of benzhydryl7-[2-(2-formamidothiazol-4-yl)-2-(L-2-benzhydryloxycarbonyl-2-tert-butoxycarbonylaminoethoxycarbonylmethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (6.9 g) in methanol (140 ml) was added conc. hydrochloricacid (3.1 ml), and the mixture was stirred at 35° C. for 90 minutes. Thereaction mixture was adjusted to pH 6.0 with 5% aqueous sodiumbicarbonate and then diluted with water (200 ml). Removal of themethanol gave an aqueous solution, which was extracted with ethylacetate. The extract was washed with an aqueous sodium chloride and thendried over anhydrous magnesium sulfate, followed by removal of thesolvent. The residue was pulverized with diisopropyl ether and collectedby filtration to obtain benzhydryl7-[2-(2-aminothiazol-4-yl)-2-(L-2-benzhydryloxycarbonyl-2-tert-butoxycarbonylaminoethoxycarbonylmethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (5.5 g), mp 124°-128° C.

IR (Nujol): 3360, 1750 (broad) cm⁻¹.

NMR δppm (DMSO-d₆): 1.40 (9H, s), 3.57, 3.98 (2H, ABq, J=18 Hz), 4.50(3H, m), 4.63 (2H, broad s), 5.30 (1, d, J=11 Hz), 5.31 (1H, d, J=5 Hz),5.67 (1H, d, J=18 Hz), 5.95 (1H, dd, J=5 Hz, 8 Hz), 6.86 (2H, s),6.8-7.20 (1H, m), 7.00 (1H, s), 7.40 (10H, s), 9.65 (1H, d, J=8 Hz).

EXAMPLE 130

To a solution of benzhydryl7-[2-(2-formamidothiazol-4-yl)-2-(DL-3-benzhydryloxycarbonyl-3-tert-butoxycarbonylaminopropoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (3.65 g) in methanol (109 ml) was added conc. hydrochloricacid (1.96 ml), and the mixture was stirred at 35° C. for 24 minutes.The reaction mixture was adjusted to pH 6.5 with 10% aqueous sodiumhydroxide and 5% aqueous sodium bicarbonate, followed by removal of themethanol. The residue was dissolved in ethyl acetate, washed with anaqueous sodium chloride and then dried over anhydrous magnesium sulfate.Removal of the solvent gave a residue, which was pulverized withdiisopropyl ether to obtain benzhydryl7-[2-(2-aminothiazol-4-yl)-2-(DL-3-benzhydryloxycarbonyl-3-tert-butoxycarbonylaminopropoxyimino)-acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (3.5 g), mp 119°-122° C.

IR (Nujol): 3300, 1780, 1719, 1680 cm⁻¹.

NMR δppm (DMSO-d₆): 1.37 (9H, s), 2.1 (2H, m), 3.7 (2H, m), 4.2 (3H, m),5.2-6.1 (4H, m), 6.8 (2H, s), 6.8-7.2 (1H, m), 6.97 (1H, s), 7.37 (20H,s), 9.67 (1H, d, J=8 Hz).

EXAMPLE 131

To a solution ofL-2-benzhydryloxycarbonyl-2-tert-butoxycarbonylaminoethyl7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (6.8 g) in methanol (300 ml) was added conc. hydrochloricacid (3.8 ml), and the mixture was stirred at 35° C. for an hour. Afteraddition of water (100 ml), the reaction mixture was adjusted to pH 5.5with an aqueous sodium bicarbonate, followed by removal of the methanol.The residue was dissolved in ethyl acetate, washed with an aqueoussodium chloride and then dried over anhydrous magnesium sulfate,followed by treating with an activated charcoal. Removal of the solventgave L-2-benzhydryloxycarbonyl-2-tert-butoxycarbonylaminoethyl7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (5.0 g).

IR (Nujol): 3370, 1775, 1730, 1616 cm⁻¹.

NMR δppm (DMSO-d₆): 1.33 (9H, s), 3.83, 3.93 (2H, ABq, J=18 Hz), 3.80(3H, s), 4.47 (3H, broad s), 5.12 (1H, d, J=5 Hz), 5.23 (1H, d, J=11Hz), 5.60 (1H, dd, J=5 Hz, 8 Hz), 5.66 (1H, d, J=18 Hz), 6.70 (1H, s),6.77 (1H, s), 6.8-7.2 (1H, m), 7.3 (10H, broad s), 9.57 (1H, d, J=8 Hz).

EXAMPLE 132

To a solution ofL-2-benzhydryloxycarbonyl-2-tert-butoxycarbonylaminoethyl7-[(2-formamidothiazol-4-yl)-glyoxylamido]-3-vinyl-3-cephem-4-carboxylate(8.7 g) in methanol (150 ml) was added conc. hydrochloric acid (4.7 g),and the mixture was stirred at 35° to 40° C. for 70 minutes. Thereaction mixture was adjusted to pH 5.0 with 5% aqueous sodium hydroxideand 5% aqueous sodium bicarbonate, followed by adding dropwise to water(600 ml). The precipitated solid was collected by filtration, washedwith water and then dried to giveL-2-benzhydryloxycarbonyl-2-tert-butoxycarbonylaminoethyl7-[(2-aminothiazol-4-yl)-glyoxylamido]-3-vinyl-3-cephem-4-carboxylate(5.40 g).

IR (Nujol): 3340, 1775, 1720, 1660, 1614 cm⁻¹.

NMR δppm (DMSO-d₆): 1.37 (9H, s), 3.47, 3.97 (2H, ABq, J=18 Hz), 4.53(3H, m), 5.18 (1H, d, J=5 Hz), 5.33 (1H, d, J=11 Hz), 5.65 (1H, dd, J=5Hz, 8 Hz), 5.68 (1H, d, J=18 Hz), 6.82 (1H, s), 6.92 (1H, dd, J=11 Hz,18 Hz), 7.37 (10H, s), 7.83 (1H, s), 9.80 (1H, d, J=8 Hz).

EXAMPLE 133

A solution of7-[2-(2-formamidothiazol-5-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (1.9 g) and conc. hydrochloric acid (1.36 g) inmethanol (190 ml) was stirred at ambient temperature for 1.3 hours.After the reaction mixture was evaporated to dryness, the residue wassuspended in water (35 ml) and then adjusted to pH 7-8 with 10% aqueoussodium hydroxide, followed by adjusting to pH 3 with 10% hydrochloricacid. The precipitated solid was collected by filtration, washed withwater and then dried to give7-[2-(2-aminothiazol-5-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (1.3 g), mp >250° C.

IR (Nujol): 3300, 1780, 1645, 1580, 1515 cm⁻¹.

NMR δppm (DMSO-d₆): 3.76 (2H, q, J=20 Hz), 3.81 (3H, s), 5.23 (1H, d,J=5 Hz), 5.35 (1H, d, J=11 Hz), 5.60 (1H, d, J=18 Hz), 5.78 (1H, dd,J=5, 8 Hz), 6.98 (1H, dd, J=11, 18 Hz), 7.12 (1H, s), 7.60 (2H, broads), 9.76 (1H, d, J=8 Hz).

EXAMPLE 134

7-[2-(2-Aminothiazol-5-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (anti isomer) (1.27 g) was obtained by reacting7-[2-(2-formamidothiazol-5-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (anti isomer) (2.1 g) with conc. hydrochloric acid (1.5 g)according to a similar manner to that of Example 133, mp >250° C.

IR (Nujol): 3320, 1775, 1655, 1575, 1515 cm⁻¹.

NMR δppm (DMSO-d₆): 3.76 (2H, q, J=20 Hz), 4.01 (3H, s), 5.23 (1H, d,J=5 Hz), 5.33 (1H, d, J=11 Hz), 5.58 (1H, d, J=18 Hz), 5.73 (1H, dd,J=5, 8 Hz), 6.98 (1H, dd, J=11, 18 Hz), 7.72 (2H, broad s), 7.79 (1H,s), 9.27 (1H, d, J=8 Hz).

EXAMPLE 135

7-[(2-Aminothiazol-5-yl)glyoxylamido]-3-vinyl-3-cephem-4-carboxylic acid(1.1 g) was obtained by reacting7-[(2-formamidothiazol-5-yl)glyoxylamido]-3-vinyl-3-cephem-4-carboxylicacid (1.73 g) with conc. hydrochloric acid (2.2 g) according to asimilar manner to that of Example 133, mp >250° C.

IR (Nujol): 3300, 3180, 1770, 1690, 1620, 1510, 1460 cm⁻¹.

NMR δppm (DMSO-d₆): 3.75 (2H, q, J=18 Hz), 5.24 (1H, d, J=5 Hz), 5.35(1H, d, J=11 Hz), 5.62 (1H, d, J=17 Hz), 5.73 (1H, dd, J=5, 8 Hz), 7.03(1H, dd, J=11, 17 Hz), 8.28 (1H, s), 8.56 (2H, broad s), 9.54 (1H, d,J=8 Hz).

EXAMPLE 136

7-[2-(2-Aminothiazol-4-yl)-2-ethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (12.2 g) was obtained by reacting7-[2-(2-formamidothiazol-4-yl)-2-ethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (15.2 g) with conc. hydrochloric acid (14 ml)according to a similar manner to that of Example 133.

IR (Nujol): 3300, 1770, 1660, 1545 cm⁻¹.

NMR δppm (DMSO-d₆): 1.27 (3H, t, J=7 Hz), 3.77 (2H, q, J=18 Hz), 4.17(2H, q, J=7 Hz), 5.23 (1H, d, J=5 Hz), 5.35 (1H, d, J=11 Hz), 5.62 (1H,d, J=17 Hz), 5.83 (1H, dd, J=5 Hz, 8 Hz), 6.78 (1H, s), 6.98 (1H, dd,J=11 Hz, 17 Hz), 9.63 (1H, d, J=8 Hz).

EXAMPLE 137

7-[2-(2-Aminothiazol-4-yl)-2-hexyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (2.1 g) mp 147°-155° C. (dec.), was obtained byreacting7-[2-(2-formamidothiazol-4-yl)-2-hexyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (3 g) with conc. hydrochloric acid (0.65 g) accordingto a similar manner to that of Example 133.

IR (Nujol): 3250, 1770, 1660, 1530 cm⁻¹.

NMR δppm (DMSO-d₆): 0.84 (3H, t, J=6 Hz), 1.03-2.0 (8H, m), 3.70 (2H,ABq, J=18 Hz), 4.07 (2H, t, J=6 Hz), 5.20 (1H, d, J=5 Hz), 5.28 (1H, d,J=11 Hz), 5.55 (1H, d, J=17 Hz), 5.77 (1H, dd, J=5 Hz, 8 Hz), 6.70 (1H,s), 6.93 (1H, dd, J=11 Hz, 17 Hz), 9.58 (1H, d, J=8 Hz).

The following compounds were obtained by reacting 7-acylamino-3-vinylcephalosporanic acid derivatives having formamido group with conc.hydrochloric acid according to a similar manner to that of Example 133.

EXAMPLE 138

7-[2-(5-Amino-1,2,4-oxadiazol-3-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3250, 1770, 1660, 1550 cm⁻¹.

EXAMPLE 139

7-[2-(5-Amino-1,2,4-oxadiazol-3-yl)acetamido]-3-vinyl-3-cephem-4-carboxylicacid.

IR (Nujol): 3500-3200, 1770, 1690, 1670, 1565 cm⁻¹.

EXAMPLE 140

L-2-Amino-2-carboxyethyl7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 3200, 1770, 1735 (shoulder), 1650 (broad) cm⁻¹.

EXAMPLE 141

L-2-Amino-2-carboxyethyl7-[2-(2-aminothiazol-4-yl)-DL-glycolamido]-3-vinyl-3-cephem-4-carboxylate.

IR (Nujol): 3300, 3180, 1760, 1720, 1628 cm⁻¹.

EXAMPLE 142

7-[2-(2-Aminothiazol-4-yl)-2-(L-2-amino-2-carboxyethoxycarbonylmethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer), mp 158° C. (dec.).

IR (Nujol): 3200 (broad), 1760 (broad)cm⁻¹.

EXAMPLE 143

7-[2-(2-Aminothiazol-4-yl)-2-(DL-3-amino-3-carboxypropoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer), mp 145° C. (dec.).

IR (Nujol): 3120, 1766, 1612 cm⁻¹.

EXAMPLE 144

A solution of benzhydryl7-[2-(2-formamidothiazol-5-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (2.7 g) in anisole (3.5 ml) and trifluoroacetic acid (10.8ml) was stirred under ice-cooling for 15 minutes. The reaction mixturewas poured into diisopropyl ether (140 ml), followed by stirring for 10minutes. The precipitated solid was collected by filtration, washed withdiisopropyl ether and then dried to give7-[2-(2-formamidothiazol-5-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (2.0 g), mp 147° C. (dec.).

IR (Nujol): 3250, 3090, 1770, 1660, 1530 cm⁻¹.

NMR δppm (DMSO-d₆): 3.78 (2H, q, J=18 Hz), 3.92 (3H, s), 5.27 (1H, d,J=5 Hz), 5.33 (1H, d, J=11 Hz), 5.58 (1H, d, J=17 Hz), 5.82 (1H, dd,J=5,8 Hz), 6.97 (1H, dd, J=11, 17 Hz), 7.57 (1H, s), 8.57 (1H, s), 9.89(1H, d, J=8 Hz).

EXAMPLE 145

7-[2-(2-Formamidothiazol-5-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (anti isomer) (2.35 g), mp 165° C. (dec.), was obtained by reactingbenzhydryl7-[2-(2-formamidothiazol-5-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(anti isomer) (3.0 g) with trifluoroacetic acid (12 ml) in the presenceof anisole (3.9 ml) according to a similar manner to that of Example144.

IR (Nujol): 3260, 1780, 1730, 1690, 1670, 1575, 1520 cm⁻¹.

NMR δppm (DMSO-d₆): 3.75 (2H, q, J=18 Hz), 4.14 (3H, s), 5.28 (1H, d,J=5 Hz), 5.35 (1H, d, J=11 Hz), 5.62 (1H, d, J=18 Hz), 5.77 (1H, dd,J=5, 8 Hz), 7.02 (1H, dd, J=11, 18 Hz), 8.23 (1H, s), 8.60 (1H, s), 9.48(1H,d,J=8 Hz).

EXAMPLE 146

7-[(2-Formamidothiazol-5-yl)glyoxylamido]-3-vinyl-3-cephem-4-carboxylicacid (2.1 g), mp 157° C. (dec.), was obtained by reacting benzhydryl7-[(2-formamidothiazol-5-yl)glyoxylamido]-3-vinyl-3-cephem-4-carboxylate(2.9 g) with trifluoroacetic acid (11.6 ml) in the presence of anisole(3.8 ml) according to a similar manner to that of Example 144.

IR (Nujol): 3270, 1775, 1700, 1655, 1535, 1470 cm⁻¹.

NMR δppm (DMSO-d₆): 3.73 (2H, q, J=18 Hz), 5.24 (1H, d, J=5 Hz), 5.34(1H, d, J=11 Hz), 5.60 (1H, d, J=17 Hz), 5.73 (1H, dd, J=5, 8 Hz), 7.00(1H, dd, J=11, 17 Hz), 8.57 (1H, s), 8.68 (1H, s), 9.87 (1H, d, J=8 Hz).

EXAMPLE 147

7-[2-(2-Formamidothiazol-4-yl)-2-ethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (15.3 g) was obtained by reacting benzhydryl7-[2-(2-formamidothiazol-4-yl)-2-ethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (24.7 g) with trifluoroacetic acid (45.6 g) in the presenceof anisole (17 g) according to a similar manner to that of Example 144.

IR (Nujol): 3250, 1770, 1690,1660, 1540 cm⁻¹.

NMR δppm (DMSO-d₆): 1.30 (3H, t, J=7 Hz), 3.77 (2H, q, J=17 Hz), 4.22(2H, q, J=7 Hz), 5.27 (1H, d, J=5 Hz), 5.36 (1H, d, J=11 Hz), 5.62 (1H,d, J=17 Hz), 5.88 (1H, dd, J=5 Hz, 8 Hz), 6.98 (1H, dd, J=11 Hz, 17 Hz),7.43 (1H, s), 8.55 (1H, s), 9.70 (1H, d, J=8 Hz), 12.47 (1H, broad s).

EXAMPLE 148

7-[2-(2-Formamidothiazol-4-yl)-2-hexyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (3.1 g) was obtained by reacting benzhydryl7-[2-(2-formamidothiazol-4-yl)-2-hexyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (5.5 g) with trifluoroacetic acid (9.3 g) in the presenceof anisole (3.5 g) according to a similar manner to that of Example 144.

IR (Nujol): 3250, 1780, 1700, 1685 (shoulder), 1650, 1570, 1550 cm⁻¹.

NMR δppm (DMSO-d₆): 0.88 (3H, t, J=6 Hz), 1.07-2.0 (8H, m), 3.72 (2H,ABq, J=18 Hz), 4.13 (2H, t, J=6 Hz), 5.23 (1H, d, J=5 Hz), 5.37 (1H, d,J=11 Hz), 5.60 (1H, d, J=17 Hz), 5.83 (1H, dd, J=5 Hz, 8 Hz), 6.97 (1H,dd, J=11 Hz, 17 Hz), 7.40 (1H, s), 8.53 (1H, s), 9.65 (1H, d, J=8 Hz),12.62 (1H, broad s).

The following compounds were obtained by reacting 7-acylamino-3-vinylcephalosporanic acid derivatives having benzhydryloxycarbonyl withtrifluoroacetic acid in the presence of anisole according to a similarmanner to that of Example 144.

EXAMPLE 149

7-[2-(2-Aminothiazol-5-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer), mp >250° C.

IR (Nujol): 3300, 1780, 1645, 1580, 1515 cm⁻¹.

EXAMPLE 150

7-[2-(2-Aminothiazol-5-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (anti isomer), mp >250° C.

IR (Nujol): 3320, 1775, 1655, 1575, 1515 cm⁻¹.

EXAMPLE 151

7-[(2-Aminothiazol-5-yl)glyoxylamido]-3-vinyl-3-cephem-4-carboxylicacid, mp >250° C.

IR (Nujol): 3300, 3180, 1770, 1690, 1620, 1510, 1460 cm⁻¹.

EXAMPLE 152

7-[2-(2-Aminothiazol-4-yl)-2-ethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3300, 1770, 1660, 1545 cm⁻¹.

EXAMPLE 153

7-[2-(2-Aminothiazol-4-yl)-2-hexyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer), mp 147°-155° C. (dec.).

IR (Nujol): 3250, 1770, 1660, 1530 cm⁻¹.

EXAMPLE 154

To a suspension of benzhydryl7-[2-(5-amino-1,2,4-oxadiazol-3-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(2.4 g) in methylene chloride (15 ml) and anisole (1.8 g) was addedtrifluoroacetic acid (4.9 g), and the mixture was stirred at ambienttemperature for an hour. To the reaction mixture was added diisopropylether (150 ml), and the precipitated material was collected byfiltration, followed by suspension in a mixture of ethyl acetate andwater, and adjusting to pH 7 with 10% aqueous sodium hydroxide. To theseparated aqueous solution was added ethyl acetate and saturated withsodium chloride. After adjusting to pH 1.5 with 10% hydrochloric acid,the ethyl acetate solution was separated, washed with a saturatedaqueous sodium chloride and then dried over anhydrous magnesium sulfate.Removal of the solvent gave a residue, which was washed with diethylether to obtain7-[2-(5-amino-1,2,4-oxadiazol-3-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (1.6 g).

IR (Nujol): 3250, 1770, 1660, 1550 cm⁻¹.

NMR δppm (DMSO-d₆): 3.77 (2H, q, J=17 Hz), 4.00 (3H, s), 5.23 (1H, d,J=5 Hz), 5.37 (1H, d, J=11 Hz), 5.62 (1H, d, J=17 Hz), 5.85 (1H, dd, J=5Hz, 8 Hz), 7.00 (1H, dd, J=11 hz, 17 Hz), 8.07 (2H, s), 9.78 (1H, d, J=8Hz).

EXAMPLE 155

7-[2-[5-{N-(N,N-Dimethylaminomethylene)amino}-1,2,4-oxadiazol-3-yl]-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (2.2 g) was obtained by reacting benzhydryl7-[2-[5-{N-(N,N-dimethylaminomethylene)amino}-1,2,4-oxadiazol-3-yl]-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (3.3 g) with trifluoroacetic acid (5.93 g) in the presenceof anisole (2.2 g) according to a similar manner to that of Example 154.

IR (Nujol): 3200, 1770, 1700, 1660, 1640, 1530 cm⁻¹.

NMR δppm (DMSO-d₆): 3.08 (3H, s), 3.23 (3H, s), 3.75 (2H, q, J=17 Hz),4.00 (3H, s), 5.23 (1H, d, J=5 Hz), 5.37 (1H, d, J=11 Hz), 5.60 (1H, d,J=17 Hz), 5.85 (1H, dd, J=5 Hz, 8 Hz, 6.99 (1H, dd, J=11 Hz, 17 Hz),8.65 (1H, s), 9.78 (1H, d, J=8 Hz).

EXAMPLE 156

7-[2-(5-Amino-1,2,4-oxadiazol-3-yl)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (0.55 g) was obtained by reacting benzhydryl7-[2-(5-amino-1,2,4-oxadiazol-3-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate(2.05 g) with trifluoroacetic acid (9.0 g) in the presence of anisole(2.5 g) according to a similar manner to that of Example 154.

IR (Nujol): 3500-3200, 1770, 1690, 1670, 1565 cm⁻¹.

NMR δppm (DMSO-d₆): 3.50 (2H, s), 3.73 (2H, q, J=17 Hz), 5.18 (1H, d,J=5 Hz), 5.35 (1H, d, J=11 Hz), 5.62 (1H, d, J=18 Hz), 5.75 (1H, dd, J=5Hz, 8 Hz), 7.02 (1H, dd, J=11 Hz, 18 Hz), 7.80 (2H, s), 9.22 (1H, d, J=8Hz).

EXAMPLE 157

(1)7-[2-(2-Aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (1.8 g) and sodium bicarbonate (667 mg) were dissolvedin water (40 ml) and the solution was lyophilized and then dried toprepare disodium salts of7-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (1.9 g).

IR (Nujol): 3300 (broad), 3180 (broad), 1750, 1660, 1535 cm⁻¹.

NMR δppm (DMSO-d₆): 3.42 (2H, broad s), 4.37 (2H, broad s), 5.10 (1H, d,J=5 Hz), 4.6-5.9 (3H,m), 6.89 (1H,s), 6.6-7.3 (1H,m), 7.33 (2H, broad s)mp >250° C.

(2) To a solution of the above product (1.8 g) in N,N-dimethylformamide(18 ml) was added iodomethyl pivalate (1.84 g) in N,N-dimethylformamide(1.8 ml) under ice-cooling, followed by stirring at the same temperaturefor 15 minutes. After the reaction mixture was poured into a mixture ofice-water and ethyl acetate, the organic layer was separated out. Theremained aqueous layer was extracted with ethyl acetate and the combinedethyl acetate solution was washed with an aqueous sodium bicarbonate andan aqueous sodium chloride, followed by drying over anhydrous magnesiumsulfate. Removal of the solvent gave a residue, which was pulverizedwith diisopropyl ether, followed by collecting by filtration to obtainpivaloyloxymethyl7-[2-(2-aminothiazol-4-yl)-2-(pivaloyloxymethoxycarbonylmethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (0.9 g), mp 115° C. (dec.).

IR (Nujol): 3400, 3260, 3100, 1780, 1750, 1660, 1530 cm⁻¹.

NMR δppm (DMSO-d₆): 1.06 (18H, s), 3.77 (2H, q, J=18 Hz), 4.76 (2H, s),5.25 (1H, d, J=5 Hz), 5.4-6.1 (7H, m), 6.5-7.2 (1H, m), 6.82 (1H, s),7.24 (2H, broad s), 9.59 (1H, d, J=8 Hz).

EXAMPLE 158

To a solution of sodium7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (2.2 g) in N,N-dimethylformamide (25 ml) was added dropwisea solution of iodomethyl acetate (1 g) in N,N-dimethylformamide (3 ml)below 5° C. in the course of 2 minutes, and the mixture was stirred atthe same temperature for 15 minutes. The reaction mixture was pouredinto a mixture of water (100 ml) and ethyl acetate (50 ml), and theseparated aqueous solution was extracted with ethyl acetate (30 ml). Thecombined ethyl acetate solution was washed twice with 5% aqueous sodiumbicarbonate and twice with an aqueous sodium chloride, and then driedover anhydrous magnesium sulfate. Removal of the solvent gave a residue,which was pulverized with diisopropyl ether and collected by filtrationto obtain acetoxymethyl7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (1.6 g), mp 78°-83° C.

IR (Nujol): 3300, 1765 (broad), 1660, 1610, 1535 cm⁻¹

NMR δppm (DMSO-d₆): 2.10 (3H, s), 3.77 (2H, ABq, J=18 Hz), 3.87 (3H, s),5.25 (1H, d, J=5 Hz), 5.38 (1H, d, J=11 Hz), 5.67 (1H, d, J=17 Hz), 5.85(3H, m), 6.77 (1H, s), 6.90 (1H, dd, J=11 Hz, 17 Hz), 9.80 (1H, d, J=8Hz).

EXAMPLE 159

Propionyloxymethyl7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (1.5 g), mp 79°-85° C., was obtained by reacting sodium7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (1.5 g) with iodomethyl propionate (0.82 g) according to asimilar manner to that of Example 158.

IR (Nujol): 3350, 1770 (broad), 1650, 1620, 1530 cm⁻¹.

NMR δppm (DMSO-d₆): 1.03 (3H, t, J=7 Hz), 2.40 (2H, q, J=7 Hz), 3.77(2H, ABq, J=17 Hz), 3.85 (3H, s), 5.38 (1H, d, J=11 Hz), 5.62 (1H, d,J=17 Hz), 5.85 (3H, m), 6.75 (1H, s), 6.85 (1H, dd, J=11 Hz, 17 Hz),9.62 (1H, d, J=8 Hz).

EXAMPLE 160

Isobutyryloxymethyl7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (2.3 g), mp 92°-100° C. (dec.), was obtained by reactingsodium7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (3.0 g) with iodomethyl isobutyrate (1.7 g) according to asimilar manner to that of Example 158.

IR (Nujol): 3400-3100, 1780-1740, 1670, 1610, 1530 cm⁻¹.

NMR δppm (DMSO-d₆): 1.1 (6H, d, J=6 Hz), 2.3-2.9 (1H, m), 3.46-4.23 (2H,m), 3.85 (3H, s), 5.25 (1H, d, J=5 Hz), 5.38 (1H, d, J=11 Hz), 5.52-6.0(2H, m), 5.87 (2H, s), 6.77 (1H, s), 6.85 (1H, dd, J=11 Hz, 17 Hz), 9.63(1H, d, J=8 Hz).

EXAMPLE 161

Pivaloyloxymethyl7-[2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (2.6 g) was obtained by reacting sodium7-[2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (3.56 g) with iodomethyl pivalate (1.94 g) according to asimilar manner to that of Example 158.

IR (Nujol): 3300, 1780, 1740, 1670, 1610, 1530 cm⁻¹.

NMR δppm (DMSO-d₆): 1.17 (9H, s), 1.23 (3H, t, J=6 Hz), 3.77 (2H, q,J=17 Hz), 4.12 (2H, q, J=6 Hz), 5.23 (1H, d, J=5 Hz), 5.38 (1H, d, J=11Hz), 5.62 (1H, d, J=17 Hz), 5.73 (3H, m), 6.73 (1H, s), 6.83 (1H, dd,J=11 Hz, 17 Hz), 9.57 (1H, d, J=8 Hz).

EXAMPLE 162

Hexanoyloxymethyl7-[2-(2-aminothiazol-4-yl)-DL-glycolamido]-3-vinyl-3-cephem-4-carboxylate(1.86 g) was obtained by reacting sodium7-[2-(2-aminothiazol-4-yl)-DL-glycolamido]-3-vinyl-3-cephem-4-carboxylate(2.0 g) with iodomethyl hexanoate (1.3 g) according to a similar mannerto that of Example 158, mp 65°-70° C.

IR (Nujol): 3300, 1770, 1680, 1610 cm⁻¹.

NMR δppm (DMSO-d₆): 0.61-1.80 (9H, m), 2.37 (2H, t, J=6.0 Hz), 3.40 (1H,m), 3.78 (2H, q, J=18.0 Hz), 4.90 (1H, d, J=4.0 Hz), 5.23 (1H, d, J=4.0Hz), 5.41 (1H, d, J=12.0 Hz), 5.53-6.13 (4H, m), 6.45 (1H, s), 6.88 (1H,dd, J=12.0 Hz, 18.0 Hz), 8.44 (d, J=9.0 Hz)}(1H) 8.56 (d, J=9.0 Hz).

The following compounds were obtained according to a similar manner tothat of Example 158.

EXAMPLE 163

L-2-Benzhydroyloxycarbonyl-2-tert-butoxycarbonylaminoethyl7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 3280, 1782, 1709, 1689, 1656 cm⁻¹.

EXAMPLE 164

L-2-Benzhydryloxycarbonyl-2-tert-butoxycarbonylaminoethyl7-[(2-formamidothiazol-4-yl)glyoxylamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 1777, 1720, 1667 cm⁻¹.

EXAMPLE 165

To a solution of sodium7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (2.0 g) in N,N-dimethylformamide (40 ml) was added sodiumiodide (0.8 g) and 1-bromopropyl acetate (0.9 g) under ice-cooling withstirring, and the stirring was continued at the same temperature forhalf an hour. The reaction mixture was poured into a mixture of waterand ethyl acetate, and the separated organic solution was washed twicewith a saturated aqueous sodium chloride and twice with water, followedby drying over anhydrous magnesium sulfate. Removal of the solvent gavea residue, which was pulverized with diisopropyl ether and thenchromatographed on silica gel eluting with a mixed solvent of ethylacetate and chloroform (4:6 to 6:4 by volume), and fractions containinga desired compound were collected. Removal of the solvent gave aresidue, which was pulverized with diisopropyl ether and then collectedby filtration to obtain 1-acetoxypropyl7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (0.62 g), mp 97°-101° C.

IR (Nujol): 3300, 1765, 1670, 1610 cm⁻¹.

NMR δppm (DMSO-d₆): 0.95 (3H, m), 1.87 (2H, m), 2.07 (3H, s), 3.48-4.23(2H, m), 3.85 (3H, s), 5.25 (1H, d, J=4.0 Hz), 5.25-5.98 (3H, m), 6.74(1H, s), 6.53-7.38 (4H, m), 9.58 (1H, d, J=8.0 Hz).

EXAMPLE 166

1-Acetoxypropyl7-[2-(2-aminothiazol-4-yl)-DL-glycolamido]-3-vinyl-3-cephem-4-carboxylate(0.68 g) was obtained by reacting sodium7-[2-(2-aminothiazol-4-yl)-DL-glycolamido]-3-vinyl-3-cephem-4-carboxylate(2.0 g) with 1-bromopropyl acetate (1.0 g) in the presence of sodiumiodide (0.8 g) according to a similar manner to that of Example 165.

IR (Nujol): 3300, 1770, 1680, 1620 cm⁻¹.

NMR δppm (DMSO-d₆): 0.71-1.12 (3H, m), 1.81 (2H, m), 2.05 (3H, s), 3.76(2H, q, J=18.0 Hz), 4.91 (1H, m), 5.20 (1H, d, J=5.0 Hz), 5.23-5.96 (3H,m), 6.41-7.51 (3H, m), 8.53 (1H, m).

EXAMPLE 167

To a solution ofL-2-benzhydryloxycarbonyl-2-tert-butoxycarbonylaminoethyl7-[(2-aminothiazol-4-yl)-glyoxylamido]-3-vinyl-3-cephem-4-carboxylate(5.4 g) in methanol was added bit by bit sodium borohydride (0.417 g) at5° C., and the mixture was stirred at the same temperature for 15minutes. After adjusting the reaction mixture to pH 5.0 with conc.hydrochloric acid, it was concentrated to dryness under reduced pressureto give a residue, which was chromatographed on silica gel (100 ml)eluting with a mixed solvent of benzene and acetone. Fractionscontaining a desired compound were collected and then evaporated toobtain L-2-benzhydryloxycarbonyl-2-tert-butoxycarbonylaminoethyl7-[2-(2-aminothiazol-4-yl)-DL-glycolamido]-3-vinyl-3-cephem-4-carboxylate(2.50 g).

    ______________________________________                                        IR (Nujol): 3340, 1774, 1715 cm.sup.-1                                        NMR     δppm (DMSO-d.sub.6): 1.33 (9H, s), 3.30 (1H, s),                        3.46, 3.90 (2H, ABq, J=18Hz), 4.50 (3H, m),                                   4.83 (s)                                                                       (1H),                                                                        4.92 (s)                                                                      5.1-6.0 (3H, m), 5.11 (1H, d, J=5Hz),                                         6.41 (1H, s), 6.77 (1H, s), 6.88 (1H, dd,                                     J=11Hz, 18Hz), 7.37 (10H, s,),                                                8.36 (d, J=8Hz)                                                                (1H)                                                                         8.46 (d, J=8Hz)                                                       ______________________________________                                    

EXAMPLE 168

A solution of benzhydryl7-(4-bromo-2-methoxyiminoacetoacetamido)-3-vinyl-3-cephem-4-carboxylate(syn isomer) (1.2 g), thiourea (0.5 g) and sodium acetate (trihydrate)(0.7 g) in water (20 ml) and tetrahydrofuran (20 ml) was stirred at 30°C. for 3.5 hours. The reaction mixture was extracted with ethyl acetate,and the extract was washed with water and dried over anhydrous magnesiumsulfate. Removal of the solvent gave a residue, which was pulverizedwith diethyl ether to obtain benzhydryl7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (1.05 g).

IR (Nujol): 3230, 1780, 1710, 1650, 1620, 1580, 1540 cm⁻¹.

NMR δppm (DMSO-d₆): 3.78 (2H, q, J=17 Hz), 3.87 (3H, s), 5.28 (1H, d,J=5 Hz), 5.32 (1H, d, J=11 Hz), 5.65 (1H, d, J=17 Hz), 5.72 (1H, dd, J=5Hz, 8 Hz), 6.80 (1H, s), 6.80 (1H, dd, J=11 Hz, 17 Hz), 6.97 (1H, s),7.20-7.67 (10H, m), 9.67 (1H, d, J=8 Hz)

EXAMPLE 169

7-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (0.8 g) was obtained by reacting7-(4-bromo-2-methoxyiminoacetoacetamido)-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (1.5 g) with thiourea (0.8 g) according to a similarmanner to that of Example 168.

IR (Nujol): 3400-3100, 1780, 1660, 1630, 1540 cm⁻¹.

NMR δppm (DMSO-d₆): 3.72 (2H, q, J=18 Hz), 3.87 (3H, s), 5.20 (1H, d,J=5 Hz), 5.33 (1H, d, J=11 Hz), 5.58 (1H, d, J=18 Hz), 5.78 (1H, dd, J=5Hz, 8 Hz), 6.77 (1H, s), 6.95 (1H, dd, J=11 Hz, 18 Hz), 9.62 (1H, d, J=8Hz).

The following compounds were obtained by reacting the corresponding7-acylamino-3-vinyl cephalosporanic acid derivatives with thioureaaccording to a similar manner to that of Example 168.

EXAMPLE 170

L-2-Benzhydryloxycarbonyl-2-tert-butoxycarbonylaminoethyl7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 3370, 1775, 1730, 1616 cm⁻¹.

EXAMPLE 171

7-[2-(2-Aminothiazol-4-yl)-2-ethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3300, 1770, 1660, 1545 cm⁻¹.

EXAMPLE 172

7-[2-(2-Aminothiazol-4-yl)-2-hexyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer), mp 147°-155° C. (dec).

IR (Nujol): 3250, 1770, 1660, 1530 cm⁻¹.

EXAMPLE 173

Pivaloyloxymethyl7-[2-(2-aminothiazol-4-yl)-2-(pivaloyloxymethoxycarbonylmethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer), mp 115° C. (dec.).

IR (Nujol): 3400, 3260, 3100, 1780, 1750, 1660, 1530 cm⁻¹.

EXAMPLE 174

Acetoxymethyl7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer), mp 78°-83° C.

IR (Nujol): 3300, 1765 (broad), 1660, 1610, 1535 cm⁻¹.

EXAMPLE 175

Propionyloxymethyl7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer), mp 79°-85° C.

IR (Nujol): 3350, 1770 (broad), 1650, 1620, 1530 cm⁻¹.

EXAMPLE 176

Isobutyryloxymethyl7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer), mp 92°-100° C. (dec).

IR (Nujol): 3400-3100, 1780-1740, 1670, 1610, 1530 cm⁻¹.

EXAMPLE 177

Pivaloyloxymethyl7-[2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 3300, 1780, 1740, 1670, 1610, 1530 cm⁻¹.

EXAMPLE 178

1-Acetoxypropyl7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer), mp 97°-101° C.

IR (Nujol): 3300, 1765, 1670, 1610 cm⁻¹.

EXAMPLE 179

To a mixture of trifluoroacetic acid (28.8 ml) and anisole (4.8 ml) wasadded L-2-benzhydryloxycarbonyl-2-tert-butoxycarbonylaminoethyl7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(4.8 g) at 5° C., and the mixture was stirred at 0° to 5° C. for half anhour. The reaction mixture was added dropwise to diisopropyl ether (900ml), and the precipitated material was collected by filtration, andthereto were added water (100 ml) and ethyl acetate (100 ml). Theseparated aqueous solution was washed with ethyl acetate (50 ml),followed by completely removing the ethyl acetate therein byevaporation. The resultant aqueous solution was adjusted to pH 3.0 with5% aqueous sodium bicarbonate, followed by removal of the precipitatedmaterial. The aqueous solution was chromatographed on a nonionicadsorption resin, "Diaion HP-20" (Trade Mark, manufactured by MitsubishiChemical Industries Ltd.) (100 ml). After washing with water (300 ml),elution was carried out with 30% aqueous isopropyl alcohol and fractionscontaining a desired compound were collected. Removal of the solventgave a residue, which was lyophilized and then dried to obtainL-2-amino-2-carboxyethyl7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (1.5 g).

IR (Nujol): 3200, 1770, 1735 (shoulder), 1650 (broad) cm⁻¹.

NMR δppm (DCl+D₂ O): 3.73, 3.94 (2H, ABq, J=18 Hz), 4.13 (3H, s),4.5-4.9 (3H, m), 5.30 (1H, d, J=5 Hz), 5.56 (1H, d, J=11 Hz), 5.77 (1H,d, J=18 Hz), 5.80 (1H, d, J=5 Hz), 7.11 (1H, dd, J=11 Hz, 18 Hz), 7.19(1H, s).

EXAMPLE 180

A solution of L-2-benzhydryloxycarbonyl-2-tert-butoxycarbonylaminoethyl7-[2-(2-aminothiazol-4-yl)-DL-glycolamido]-3-vinyl-3-cephem-4-carboxylate(2.2 g) and anisole (5 ml) in trifluoroacetic acid (20 ml) was stirredat 5° C. for half an hour. The reaction mixture was added dropwise todiisopropyl ether (600 ml), and the precipitated material was collectedby filtration and then washed with diisopropyl ether, followed bydissolving in water (50 ml). After adjusting to pH 3.5 with 5% aqueoussodium bicarbonate, the aqueous solution was chromatographed on anonionic adsorption resin, "Diaion HP-20" (80 ml). After washing withwater (240 ml), elution was carried out with 10% aqueous isopropylalcohol, and fractions containing a desired compound were collected.Removal of the solvent gave a residue, which was lyophilized and thendried to obtain L-2-amino-2-carboxyethyl7-[2-(2-aminothiazol-4-yl)-DL-glycolamido]-3-vinyl-3-cephem-4-carboxylate(1.1 g).

    ______________________________________                                        IR (Nujol):                                                                   3300, 3180, 1760, 1720, 1628 cm.sup.-1                                        NMR δ ppm (DMSO-d.sub.6):                                               3.55, 3.97 (2 H, ABq, J = 18 Hz),                                             4.3-4.83 (3 H, m), 4.88 (1 H, s), 5.18 (1 H, d,                               J = 5 Hz), 5.38 (1 H, d, J = 11 Hz), 5.62 (1 H, d,                            J = 18 Hz), 5.77 (1 H, m), 6.43 (1 H, s), 6.98                                (1 H, dd, J = 11 Hz, 18 Hz),                                                  8.4 (d, J = 8 Hz)                                                              (1 H)                                                                        8.47 (d, J = 8 Hz)                                                            ______________________________________                                    

EXAMPLE 181

A mixture of benzhydryl7-[2-(2-aminothiazol-4-yl)-2-(L-2-benzhydryloxycarbonyl-2-tert-butoxycarbonylaminoethoxycarbonylmethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (5.4 g), trifluoroacetic acid (21.6 ml) and anisole (5.4ml) was stirred at 5° to 10° C. for 70 minutes. The reaction mixture wasadded dropwise to diisopropyl ether (1000 ml), followed by collectingthe precipitated material. After washing with diisopropyl ether, saidmaterial was dissolved in a mixture of ethyl acetate (50 ml) and water(50 ml). The separated aqueous solution was washed with ethyl acetate,and the ethyl acetate therein was completely removed by evaporation. Theresultant aqueous solution was adjusted to pH 3.0 with 5% sodiumbicarbonate and then chromatographed on a nonionic adsorption resin,"Diaion HP-20" (100 ml). After washing with water (300 ml), elution wascarried out 20% aqueous isopropyl alcohol, and fractions containing adesired compound were collected. Removal of the solvent gave a residue,which was lyophilized to obtain7-[2-(2-aminothiazol-4-yl)-2-(L-2-amino-2-carboxyethoxycarbonylmethoxyimino)-acetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (1.7 g), mp 158° C. (dec.).

IR (Nujol): 3200 (broad), 1760 (broad) cm⁻¹.

NMR δppm (DMSO-d₆): 3.51, 3.75 (2H, ABq, J=18 Hz), 4.3-4.8 (5H, m), 5.13(1H, d, J=5 Hz), 5.19 (1H, d, J=11 Hz), 5.44 (1H, d, J=18 Hz), 5.72 (1H,dd, J=5 Hz, 8 Hz), 6.79 (1H, s), 6.93 (1H, dd, J=11 Hz, 18 Hz), 9.66(1H, d, J=8 Hz).

EXAMPLE 182

A mixture of benzhydryl7-[2-(2-aminothiazol-4-yl)-2-(DL-3-benzhydryloxycarbonyl-3-tert-butoxycarbonylaminopropoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (3.3 g), trifluoroacetic acid (20 ml) and anisole (3.3 ml)was stirred at 5° to 10° C. for 1.5 hours. The reaction mixture wasadded dropwise to diisopropyl ether (300 ml), and the precipitatedmaterial was collected by filtration and then washed with diisopropylether, followed by dissolving in water (50 ml). The aqueous solution waswashed with ethyl acetate (50 ml×2), and the ethyl acetate therein wascompletely removed by evaporation. The resultant aqueous solution wasadjusted to pH 3.1 with 5% aqueous sodium bicarbonate andchromatographed on a nonionic adsorption resin, "Diaion HP-20" (100 ml).After washing with water (300 ml), elution was carried out with 20%aqueous isopropyl alcohol, and the fractions containing a desiredcompound were collected and then treated with an activated charcoal.Removal of the solvent gave a residue, which was lyophilized to obtain7-[2-(2-aminothiazol-4-yl)-2-(DL-3-amino-3-carboxypropoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (0.7 g), mp 145° C. (dec.).

IR (Nujol): 3120, 1766, 1612 cm⁻¹.

NMR δppm (D₂ O+DCl): 2.53 (2H, m), 3.82 (2H, broad s), 4.31 (1H, t, J=6Hz), 4.57 (2H, t, J=6 Hz), 5.32 (1H, d, J=5 Hz), 5.53 (1H, d, J=11 Hz),5.73 (1H, d, J=18 Hz), 5.82 (1H, d, J=5 Hz), 7.13 (1H, dd, J=11 Hz, 18Hz), 7.25 (1H, s).

EXAMPLE 183

To a suspension of Vilsmeier reagent, which was prepared fromN,N-dimethylformamide (1.8 g) and phosphorus oxychloride (3.7 g), intetrahydrofuran (60 ml) was added2-(2-formamidothiazol-4-yl)-2-(2-pyridylmethoxyimino)acetic acid (synisomer) (6.74 g) under ice-cooling with stirring, and the stirring wascontinued at the same temperature for 30 minutes to prepare theactivated acid solution. This solution was added to a solution ofbenzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (8.6 g)and trimethylsilylacetamide (15.7 g) in ethyl acetate (100 ml) at -20°C., and the mixture was stirred at -20° to -5° C. for 2 hours. To thereaction mixture were added ethyl acetate and water, followed byseparating the ethyl acetate layer. After the ethyl acetate solution waswashed with a saturated aqueous sodium bicarbonate and an aqueous sodiumchloride, it was dried over anhydrous magnesium sulfate. Removal of thesolvent gave a residue, which was pulverized with diisopropyl ether toobtain benzhydryl7-[2-(2-formamidothiazol-4-yl)-2-(2-pyridylmethoxyimino)-acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (13.6 g).

IR (Nujol): 3250, 1760, 1720, 1660, 1580, 1560, 1540 cm⁻¹.

NMR δppm (DMSO-d₆): 3.77 (2H, q, J=18 Hz), 5.33 (4H, m), 5.63 (1H, d,J=17 Hz), 6.03 (1H, dd, J=5 Hz, 8 Hz), 6.80 (1H, dd, J=11 Hz, 17 Hz),7.00 (1H, s), 7.13-8.00 (14H, m), 8.53 (1H, m), 8.53 (1H, s), 10.07 (1H,d, J=8 Hz), 12.7 (1H, s).

EXAMPLE 184

Benzhydryl7-[2-(2-formamidothiazol-4-yl)-2-(3-pyridylmethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (8.7 g) was obtained by reacting benzhydryl7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (8.6 g) with2-(2-formamidothiazol-4-yl)-2-(3-pyridylmethoxyimino)acetic acid (synisomer) (6.74 g) according to a similar manner to that of Example 183.

IR (Nujol): 3260, 1770, 1710, 1690, 1650, 1580, 1570, 1530 cm⁻¹.

NMR δppm (DMSO-d₆): 3.75 (2H, q, J=18 Hz), 5.27 (2H, s), 5.30 (1H, d,J=5 Hz), 5.30 (1H, d, J=11 Hz), 5.67 (1H, d, J=17 Hz), 5.97 (1H, dd, J=5Hz, 8 Hz), 6.78 (1H, dd, J=11 Hz, 17 Hz), 6.97 (1H, s), 7.20-7.67 (12H,m), 7.87 (1H, m), 8.53 (1H, s), 8.47-8.70 (2H, m), 9.88 (1H, d, J=8 Hz),12.67 (1H, broad s).

EXAMPLE 185

A mixture of benzhydryl7-[2-(2-formamidothiazol-4-yl)-2-(2-pyridylmethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (5.45 g), conc. hydrochloric acid (5 ml) and methanol (150ml) was stirred at ambient temperature for 1.5 hours. After removal ofthe solvent, to the residue were added ethyl acetate and water, followedby adjusting to pH 7 with 20% aqueous sodium carbonate. The separatedethyl acetate solution was washed with an aqueous sodium chloride andthen dried over anhydrous magnesium sulfate. Removal of the solvent gavebenzhydryl7-[2-(2-aminothiazol-4-yl)-2-(2-pyridylmethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (4.6 g).

IR (Nujol): 3240, 1775, 1720, 1670, 1610, 1590, 1540 cm⁻¹.

NMR δppm (DMSO-d₆): 3.73 (2H, q, J=17 Hz), 5.28 (2H, s), 5.28 (2H, m),5.63 (1H, d, J=17 Hz), 5.98 (1H, dd, J=5 Hz, 8 Hz), 6.82 (1H, dd, J=11Hz, 17 Hz), 6.85 (1H, s), 7.00 (1H, s), 7.1-8.00 (13H, m), 8.53 (1H, dd,J=2 Hz, 6 Hz), 10.00 (1H, d, J=8 Hz).

EXAMPLE 186 ##STR22##

Benzhydryl7-[2-(2-formamidothiazol-4-yl)-2-(2-pyridylmethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (2.72 g) was added to a solution of dimethylsulfate (0.95g) in tetrahydrofuran (120 ml), and the mixture was stirred at 43° to46° C. for 25 hours. After removal of the solvent, the residue wasdissolved in a mixture of water (30 ml), tetrahydrofuran (30 ml) andethyl acetate (50 ml), followed by separating an aqueous layer. Theremained organic solution was extracted with water, and ethanol wasadded to the combined aqueous solution. Removal of the solvent gave aresidue, which was washed with a mixture of ethanol and diethyl ether toobtain1-methyl-2-[1-(2-formamidothiazol-4-yl)-1-{N-(4-benzhydryloxycarbonyl-3-vinyl-3-cephem-7-yl)carbamoyl}-methyleneaminooxymethyl]pyridiniummethylsulfate (syn isomer) (1.7 g).

IR (Nujol): 3180, 1770, 1710, 1670, 1625, 1540 cm⁻¹.

NMR δppm (DMSO-d₆): 3.40 (3H, s), 3.73 (2H, m), 4.38 (3H, s), 5.33 (1H,d, J=5 Hz), 5.35 (1H, d, J=11 Hz), 5.65 (1H, d, J=17 Hz), 5.75 (2H, s),6.02 (1H, dd, J=5 Hz, 8 Hz), 6.80 (1H, dd, J=11 Hz, 17 Hz), 6.98 (1H,s), 7.2-7.70 (10H, m), 7.57 (1H, s), 8.55 (1H, s), 7.93-8.63 (3H, m),9.13 (1H, dd, J=2 Hz, 6 Hz), 10.00 (1H, d, J=8 Hz) ##STR23##

A solution of the object compound (1.6 g) obtained above and conc.hydrochloric acid (1 ml) in methanol (30 ml) and tetrahydrofuran (20 ml)was stirred at ambient temperature for 5 hours. After removal of thesolvent, the residue was dissolved in tetrahydrofuran and ethanol,followed by concentration to give a residue, which was pulverized withdiethyl ether to obtain hydrochloride of1-methyl-2-[1-(2-aminothiazol-4-yl)-1-{N-(4-benzhydryloxycarbonyl-3-vinyl-3-cephem-7-yl)carbamoyl}methyleneaminooxymethyl]-pyridiniummethylsulfate (syn isomer) (1.5 g).

IR (Nujol): 1780, 1720, 1680, 1630, 1585, 1545, 1500 cm⁻¹.

NMR δppm (DMSO-d₆): 3.43 (3H, s), 3.80 (2H, m), 4.40 (3H, s), 5.33 (1H,d, J=5 Hz), 5.33 (1H, d, J=11 Hz), 5.57 (1H, d, J=17 Hz), 5.73 (2H, s),5.83 (1H, dd, J=5 Hz, 8 Hz), 6.82 (1H, dd, J=11 Hz, 17 Hz), 6.97 (1H,s), 7.07 (1H, s), 7.17-7.67 (10H, m), 7.93-8.80 (3H, m), 9.17 (1H, dd,J=2 Hz, 6 Hz), 10.08 (1H, d, J=8 Hz).

EXAMPLE 187 ##STR24##

1-Methyl-3-[1-(2-formamidothiazol-4-yl)-1-{N-(4-benzhydryloxycarbonyl-3-vinyl-3-cephem-7-yl)carbamoyl}-methyleneaminooxymethyl]pyridiniummethylsulfate (syn isomer) (2.6 g) was obtained by reacting benzhydryl7-[2-(2-formamidothiazol-4-yl)-2-(3-pyridylmethoxyimino)-acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (3.4 g) with dimethylsulfate (1.26 g) according to asimilar manner to that of Example 186-(1).

IR (Nujol): 1770, 1720, 1670, 1550 cm⁻¹.

NMR δppm (DMSO-d₆): 3.42 (3H, s), 3.80 (2H, m), 4.40 (3H, s), 5.33 (1H,d, J=5 Hz), 5.38 (1H, d, J=11 Hz), 5.52 (2H, s), 5.70 (1H, d, J=17 Hz),5.95 (1H, dd, J=5 Hz, 8 Hz), 6.82 (1H, dd, J=11 Hz, 17 Hz), 7.00 (1H,s), 7.13-7.67 (10H, m), 7.58 (1H, s), 8.17 (1H, m), 8.57 (1H, s), 8.67(1H, m), 9.03 (1H, m), 9.03 (1H, s), 9.95 (1H, d, J=8 Hz). ##STR25##

Hydrochloride of1-methyl-3-[1-(2-aminothiazol-4-yl)-1-{N-(4-benzhydryloxycarbonyl-3-vinyl-3-cephem-7-yl)carbamoyl}methyleneaminooxymethyl]-pyridiniummethylsulfate (syn isomer) (1.1 g) was obtained by reacting the objectcompound (1.5 g) obtained above with conc. hydrochloric acid (1.2 ml)according to a similar manner to that of Example 186-(2).

IR (Nujol): 3400-3100, 1760, 1660, 1600, 1530 cm⁻¹.

NMR δppm (DMSO-d₆): 3.40 (3H, s), 3.73 (2H, broad s), 4.45 (3H, s), 5.20(1H, d, J=5 Hz), 5.38 (1H, d, J=11 Hz), 5.47 (2H, s), 5.63 (1H, d, J=17Hz), 5.80 (1H, dd, J=5 Hz, 8 Hz), 6.7-7.7 (11H, m), 6.97 (1H, s), 7.12(1H, s), 8.17 (1H, m), 8.7 (1H, m), 9.00 (1H, m), 9.17 (1H, broad s),10.02 (1H, d, J=8 Hz).

EXAMPLE 188

To a solution of benzhydryl7-[2-(2-aminothiazol-4-yl)-2-(2-pyridylmethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (4.6 g) in methylene chloride (20 ml) and anisole (3.0 g)was added trifluoroacetic acid (11.2 g) under ice-cooling with stirring,and the stirring was continued at ambient temperature for 1.5 hours. Thereaction mixture was added dropwise to diisopropyl ether (300 ml) andthe precipitated crystals were collected by filtration, followed bysuspending in water (70 ml). After adjusting to pH 7.5 with 1N aqueoussodium hydroxide, the resultant aqueous solution was washed with ethylacetate. The aqueous solution was further adjusted to pH 3.4 with 10%hydrochloric acid, followed by collecting the precipitated crystals toobtain7-[2-(2-aminothiazol-4-yl)-2-(2-pyridylmethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (1.8 g).

IR (Nujol): 3300, 1770, 1650, 1620 (shoulder), 1540 cm⁻¹.

NMR δppm (DMSO-d₆): 3.70 (2H, q, J=18 Hz), 5.23 (1H, d, J=5 Hz), 5.30(2H, s), 5.32 (1H, d, J=11 Hz), 5.60 (1H, d, J=17 Hz), 5.85 (1H, dd, J=5Hz, 8 Hz), 6.82 (1H, dd, J=11 Hz, 17 Hz), 6.82 (1H, s), 7.00-8.10 (3H,m), 8.57 (1H, d, J=4 Hz), 9.97 (1H, d, J=8 Hz).

EXAMPLE 189 ##STR26##

Hydrochloride of1-methyl-2-[1-(2-aminothiazol-4-yl)-1-{N-(4-benzhydryloxycarbonyl-3-vinyl-3-cephem-7-yl)carbamoyl}methyleneaminooxymethyl]-pyridiniummethylsulfate (syn isomer) (2.6 g) was suspended in methylene chloride(20 ml) and anisole (1.4 g), and thereto was added trifluoroacetic acid(5.8 g) under ice-cooling with stirring, followed by stirring at ambienttemperature for 1.5 hours. After the reaction mixture was added dropwiseto diisopropyl ether (250 ml), the precipitated materials were collectedby filtration and dissolved in water (20 ml). The aqueous solution wasadjusted to pH 6.5 with 1N aqueous sodium hydroxide and washed withethyl acetate, and then adjusted to pH 2 with 10% hydrochloric acid,followed by subjecting to column chromatography on nonionic adsorptionresin "Diaion HP-20" (100 ml). After washing with water, elution wascarried out with 30% aqueous isopropyl alcohol, and fractions containinga desired compound were collected and evaporated. The residue obtainedwas lyophilized to obtain hydrochloride of7-[2-(2-aminothiazol-4-yl)-2-{(1-methyl-2-pyridinio)-methoxyimino}acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (1.2 g).

IR (Nujol): 1770, 1720, 1670, 1630, 1540 cm⁻¹.

NMR δppm (D₂ O): 3.60 (2H, broad s), 4.38 (3H, s), 5.22 (1H, d, J=5 Hz),5.25 (1H, d, J=11 Hz), 5.40 (1H, d, J=17 Hz), 5.70 (2H, s), 5.82 (1H, d,J=5 Hz), 6.82 (1H, dd, J=11 Hz, 17 Hz), 7.03 (1H, s), 7.80-8.73 (3H, m),8.87 (1H, dd, J=2 Hz, 6 Hz).

EXAMPLE 190 ##STR27##

Hydrochloride of7-[2-(2-aminothiazol-4-yl)-2-{(1-methyl-3-pyridino)methoxyimino}acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (0.4 g) was obtained by reacting hydrochloride of1-methyl-3-[1-(2-aminothiazol-4-yl)-1-{N-(4-benzhydryloxycarbonyl-3-vinyl-3-cephem-7-yl)carbamoyl}methyleneaminooxymethyl]-pyridiniummethylsulfate (syn isomer) (1.0 g) with trifluoroacetic acid (2.8 g) inthe presence of anisole (0.52 g) according to a similar manner to thatof Example 189.

IR (Nujol): 3400-3100, 1760, 1660, 1600, 1530 cm⁻¹.

NMR δppm (D₂ O): 3.67 (2H, broad s), 4.43 (3H, s), 5.25 (1H, d J=5 Hz),5.30 (1H, d, J=11 Hz), 5.43 (1H, d, J=17 Hz), 5.50 (2H, s), 5.80 (1H, d,J=5 Hz), 6.83 (1H, dd, J=11 Hz, 17 Hz), 7.02 (1H, s), 8.10 (1H, m),8.78-8.90 (2H, m), 8.90 (1H, s).

EXAMPLE 191

Benzhydryl7-[2-(2-formamidothiazol-4-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (4.93 g) was obtained by reacting benzhydryl7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (3.2 g) with2-(2-formamidothiazol-4-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)aceticacid (syn isomer) (2.9 g) according to a similar manner to that ofExample 103.

IR (Nujol): 3150, 1780, 1720, 1690 cm⁻¹.

NMR δppm (DMSO-d₆): 1.27-1.81 (15H, m), 3.81 (2H, q, J=18.0 Hz), 5.34(1H, d, J=4.0 Hz), 5.22-6.18 (3H, m), 6.79 (1H, dd, J=12.0 Hz, 18.0 Hz),7.00 (1H, s), 7.13-7.75 (11H, m), 8.54 (1H, s), 9.58 (1H, d, J=8.0 Hz).

EXAMPLE 192

Benzhydryl7-[2-(2-formamidothiazol-4-yl)-2-(1-tert-butoxycarbonylethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (5.62 g) was obtained by reacting benzhydryl7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (3.4 g) with2-(2-formamidothiazol-4-yl)-2-(1-tert-butoxycarbonylethoxyimino)aceticacid (syn isomer) (3.0 g) according to a similar manner to that ofExample 103.

    ______________________________________                                        IR (Nujol):                                                                   3250, 3150, 1780, 1720, 1680 cm.sup.-1                                        NMR δ ppm (DMSO-d.sub.6):                                               1.23-1.72 (12 H, m), 3.78 (2 H,                                               q, J = 18.0 Hz), 4.66 (1 H, q, J = 8.0 Hz),                                   5.33 (1 H, d, J = 5.0 Hz), 3.27-6.16 (1 H, m),                                6.79 (1 H, dd, J = 10.0 Hz, 18.0 Hz), 6.98                                    (1 H, s), 7.18-7.82 (11 H, m), 8.56 (1 H, s),                                 9.59 (d, J = 8.0 Hz)                                                           (1 H)                                                                        9.67 (d, J = 8.0 Hz)                                                          ______________________________________                                    

EXAMPLE 193

Benzhydryl7-[2-(2-formamidothiazol-4-yl)-2-ethoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (6.4 g) was obtained by reacting benzhydryl7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (4.29 g) with2-(2-formamidothiazol-4-yl)-2-ethoxycarbonylmethoxyiminoacetic acid (synisomer) (3.3 g) according to a similar manner to that of Example 103.

IR (Nujol): 3250, 1780, 1710, 1690, 1660, 1540 cm⁻¹.

NMR δppm (DMSO-d₆): 1.20 (3H, t, J=7 Hz), 3.77 (2H, m), 4.15 (2H, q, J=7Hz), 4.75 (2H, s), 5.28 (1H, d, J=11 Hz), 5.30 (1H, d, J=5 Hz), 5.65(1H, d, J=17 Hz), 5.97 (1H, dd, J=5 Hz, 8 Hz), 6.82 (1H, dd, J=11 Hz, 17Hz), 6.97 (1H, s), 7.17-7.67 (11H, m), 8.55 (1H, s), 9.73 (1H, d, J=8Hz), 12.67 (1H, broad s).

EXAMPLE 194

7-[2-(2-Formamidothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (2.7 g) was obtained by reacting7-amino-3-vinyl-3-cephem-4-carboxylic acid (2.26 g) with2-(2-formamidothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetic acid(syn isomer) (3.29 g) according to a similar manner to that of Example103.

IR (Nujol): 3230, 1780, 1720, 1680, 1542 cm⁻¹.

NMR δppm (DMSO-d₆): 1.45 (9H, s), 3.73 (2H, q, J=18 Hz), 4.63 (2H, s),5.23 (1H, d, J=5 Hz), 5.30 (1H, d, J=11 Hz), 5.58 (1H, d, J=18 Hz), 5.85(1H, dd, J=5 Hz, 8 Hz), 6.98 (1H, dd, J=11 Hz, 18 Hz), 7.46 (1H, s),8.53 (1H, s), 9.63 (1H, d, J=8 Hz), 12.73 (1H, broad s).

EXAMPLE 195

Benzhydryl7-[2-(2-aminothiazol-4-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (4.03 g) was obtained by reacting benzhydryl7-[2-(2-formamidothiazol-4-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (4.8 g) with conc. hydrochloric acid (1.4 g) according to asimilar manner to that of Example 129.

IR (Nujol): 3260, 1780, 1720, 1680, 1620 cm⁻¹.

NMR δppm (DMSO-d₆): 1.21-1.70 (15H, m), 3.83 (2H, m), 5.30 (1H, d, J=4.0Hz), 5.16-6.10 (2H, m), 6.94 (1H, dd, J=4.0 Hz, 8.0 Hz), 6.44-7.04 (1H,m), 6.74 (1H, s), 6.96 (1H, s), 7.07-7.66 (10H, m), 9.41 (1H, d, J=8.0Hz).

EXAMPLE 196

Benzhydryl7-[2-(2-aminothiazol-4-yl)-2-(1-tert-butoxycarbonylethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (4.81 g) was obtained by reacting benzhydryl7-[2-(2-formamidothiazol-4-yl)-2-(1-tert-butoxycarbonylethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (5.5 g) with conc. hydrochloric acid (1.6 g) according to asimilar manner to that of Example 129.

    ______________________________________                                        IR (Nujol):                                                                   3250, 1780, 1720, 1680, 1640, 1620 cm.sup.-1                                  NMR δ ppm (DMSO-d.sub.6):                                               1.27-1.50 (12 H, m), 3.78 -(2 H, m), 4.65 (1 H, q, J = 7.0 Hz), 5.18-         5.86 (3 H, m), 5.93 (1 H, dd, J = 5.0 Hz,                                     8.0 Hz), 6.80 (1 H, s), 6.96 (1 H, s),                                        7.07-7.67 (10 H, m),                                                          9.44 (d, J = 8.0 Hz)                                                           (1 H)                                                                        9.54 (d, J = 8.0 Hz)                                                          ______________________________________                                    

EXAMPLE 197

Benzhydryl7-[2-(2-aminothiazol-4-yl)-2-ethoxycarbonylmethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (5.45 g) was obtained by reacting benzhydryl7-[2-(2-formamidothiazol-4-yl)-2-ethoxycarbonylmethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (6.2 g) with conc.hydrochloric acid (3.8 ml) according to asimilar manner to that of Example 129.

IR (Nujol): 3250, 1780, 1720, 1662, 1620, 1535 cm⁻¹.

NMR δppm (DMSO-d₆): 1.2 (3H, t, J=7 Hz), 3.68 (2H, m), 4.15 (2H, q, J=7Hz), 5.28 (1H, d, J=11 Hz), 5.65 (1H, d, J=17 Hz), 5.95 (1H, dd, J=5 Hz,8 Hz), 6.82 (1H, dd, J=11 Hz, 17 Hz), 6.87 (1H, s), 7.00 (1H, s),7.30-7.70 (10H, m), 9.65 (1H, d, J=8 Hz).

EXAMPLE 198

7-[2-(2-Aminothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (1.7 g) was obtained by reacting7-[2-(2-formamidothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (2.1 g) with conc. hydrochloric acid (1.2 ml)according to a similar manner to that of Example 129.

IR (Nujol): 3300, 1770, 1725, 1680, 1610, 1530 cm⁻¹.

NMR δppm (DMSO-d₆): 1.45 (9H, s), 3.72 (2H, q, J=18 Hz), 4.58 (2H, s),5.22 (1H, d, J=5 Hz), 5.33 (1H, d, J=12 Hz), 5.58 (1H, d, J=18 Hz), 5.82(1H, dd, J=5 Hz, 8 Hz), 6.82 (1H, s), 6.98 (1H, dd, J=12 Hz, 18 Hz),9.52 (1H, d, J=8 Hz).

EXAMPLE 199

To a mixture of benzhydryl7-[2-(2-aminothiazol-4-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (3.9 g) and anisole (3.9 ml) was added trifluoroacetic acid(15.6 ml) under ice-cooling, and the mixture was stirred at ambienttemperature for an hour. To the reaction mixture was added diisopropylether and the precipitated crystals were collected by filtration andthen washed with diisopropyl ether. To the crystals were added ethylacetate and water, followed by adjusting to pH 7.5 with sodiumbicarbonate. The separated aqueous solution was washed with ethylacetate and then adjusted to pH 2.5 with 10% hydrochloric acid. Theprecipitated crystals were collected by filtration, washed with waterand then dried to obtain7-[2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (1.09 g), mp 173°-177° C. (dec.). The filtrate and thewashings were combined and saturated with sodium chloride, followed byextraction with tetrahydrofuran. The extract was washed with a saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate and thenevaporated to dryness to give a residue, which was pulverized withdiisopropyl ether and collected by filtration to recover the same objectcompound (0.59 g). Total yield: 1.68 g.

IR (Nujol): 3300, 3200, 1770, 1670, 1640 cm⁻¹.

NMR δppm (DMSO-d₆): 1.49 (6H, s), 3.76 (2H, q, J=18.0 Hz), 5.24 (1H, d,J=4.0 Hz), 5.18-5.98 (3H, m), 6.79 (1H, s), 6.95 (1H, dd, J=12.0 Hz,18.0 Hz), 9.41 (1H, d, J=8.0 Hz).

EXAMPLE 200

7-[2-(2-Aminothiazol-4-yl)-2-(1-carboxyethoxyimino)-acetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (0.73 g) was obtained by reacting benzhydryl7-[2-(2-aminothiazol-4-yl)-2-(1-tert-butoxycarbonylethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (4.7 g) with trifluoroacetic acid (18.8 ml) in the presenceof anisole (4.7 ml) according to a similar manner to that of Example199.

    ______________________________________                                        IR (Nujol):                                                                   3260, 3160, 1770, 1670 cm.sup.-1                                              NMR δ ppm (DMSO-d.sub.6):                                               1.44 (3 H, d, J = 7.0 Hz),                                                    3.73 (2 H, m), 4.66 (1 H, q, J = 7.0 Hz),                                     5.23 (1 H, d, J = 5.0 Hz), 5.33 (1 H, d,                                      J = 11.5 Hz), 5.63-6.00 (2 H, m), 6.81 (1 H,s),                               6.97 (1 H, dd, J = 11.5 Hz, 18.0 Hz),                                         9.44 (d, J = 8.0 Hz)                                                           (1 H)                                                                        9.49 (d, J = 8.0 Hz)                                                          ______________________________________                                    

EXAMPLE 201

7-[2-(2-Aminothiazol-4-yl)-2-ethoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (3.2 g) was obtained by reacting benzhydryl7-[2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (5.2 g) with trifluoroacetic acid (12.8 g) in the presenceof anisole (3.4 g) according to a similar manner to that of Example 144.

IR (Nujol): 3250, 1770, 1670, 1530 cm⁻¹.

NMR δppm (DMSO-d₆): 1.22 (3H, t, J=7 Hz), 3.70 (2H, broad s), 4.17 (2H,q, J=7 Hz), 4.75 (2H, s), 5.23 (1H, d, J=5 Hz), 5.35 (1H, d, J=11 Hz),5.58 (1H, d, J=17 Hz), 5.82 (1H, dd, J=5 Hz, 8 Hz), 6.88 (1H, s), 6.98(1H, dd, J=11 Hz, 17 Hz), 9.63 (1H, d, J=8 Hz).

EXAMPLE 202

Benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (2.3 g)was dissolved in dried ethyl acetate (50 ml) and trimethylsilylacetamide(4.9 g) at 40° C.

On the other hand, to a Vilsmeier reagent, which was prepared byreacting dried N,N-dimethylformamide (0.5 g) with phosphorus oxychloride(1.1 g) in dried ethyl acetate (2.0 ml) in a conventional manner, wereadded dried tetrahydrofuran (20 ml) and2-(3-tert-butoxycarbonylpropoxyimino)-2-(2-formamidothiazol-4-yl)aceticacid (syn isomer) (2.1 g), followed by stirring at -3° to 3° C. for awhile to prepare the activated acid solution.

This solution was added to the ethyl acetate solution obtained before at-10° C. with stirring, and the stirring was continued at -10° to -5° C.for half an hour. To the reaction mixture was added water, and theseparated organic layer was washed with a saturated aqueous sodiumbicarbonate and a saturated aqueous sodium chloride, followed by dryingover magnesium sulfate. Removal of the solvent gave a residue, which waspulverized with diisopropyl ether to obtain benzhydryl7-[2-(3-tert-butoxycarbonylpropoxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (3.63 g).

IR (Nujol): 3280, 3150, 1780, 1720, 1660 cm⁻¹.

NMR δppm (DMSO-d₆): 1.43 (9H, s), 1.97 (2H, m), 2.38 (2H, t, J=6.0 Hz),3.79 (2H, q, J=18.0 Hz), 4.18 (2H, t, J=6.0 Hz), 5.33 (1H, d, J=11.0Hz), 5.34 (1H, d, J=5.0 Hz), 5.67 (1H, d, J=17.0 Hz), 5.97 (1H, dd,J=5.0 Hz, 8.0 Hz), 6.82 (1H, dd, J=11.0 Hz, 17.0 Hz), 7.00 (1H, s),7.19-7.73 (11H, m), 8.57 (1H, s), 9.77 (1H, d, J=8.0 Hz).

EXAMPLE 203

Benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (10.6 g)was dissolved in methylene chloride (100 ml) and trimethylsilylacetamide(20.6 g) at 25° C.

On the other hand, to a suspension of2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetic acid (syn isomer)(4.0 g) in methylene chloride (100 ml) was added phosphorus oxychloride(12.1 g), followed by stirring at ambient temperature for 1.5 hours.Thereto was added N,N-dimethylformamide (8 ml) at -12° to -10° C., andthe mixture was stirred at -10° to -8° C. for 45 minutes to prepare theactivated acid solution.

The activated acid solution was added to the methylene chloride solutionobtained before at -30° C. with stirring, and the stirring was continuedat -15° C. for 45 minutes. The reaction mixture was poured into asaturated aqueous sodium bicarbonate (300 ml), followed by stirring forhalf an hour. During the stirring, the reaction mixture was adjusted topH 7.5 with sodium bicarbonate. Thereto was added ethyl acetate (500ml), and the insoluble substance was removed by filtration. Theseparated organic layer was washed with an aqueous sodium chloride andthen dried over magnesium sulfate. Removal of the solvent gave aresidue, which was pulverized with diethyl ether to obtain benzhydryl7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (6.3 g).

IR (Nujol): 3300, 3175, 1770, 1720, 1670, 1610, 1590 cm⁻¹.

NMR δppm (DMSO-d₆): 3.77 (2H, m), 3.93 (3H, s), 5.25 (1H, d, J=5 Hz),5.27 (1H, d, J=11 Hz), 5.62 (1H, d, J=17 Hz), 5.92 (1H, dd, J=5 Hz, 8Hz), 6.77 (1H, dd, J=11 Hz, 17 Hz), 6.97(1H, s), 7.38(10H, m), 9.62 (1H,d, J=8 Hz).

EXAMPLE 204

Vilsmeier reagent, which was prepared from N,N-dimethylformamide (0.37ml) and phosphorus oxychloride (0.44 ml) in a conventional manner, wassuspended in dried tetrahydrofuran (20 ml).2-(tert-Butoxycarbonylmethoxyimino)-2-(6-formamidopyridin-2-yl)aceticacid (syn isomer) (3.0 g) was added thereto under ice-cooling withstirring, and the stirring was continued at the same temperature for anhour to prepare the activated acid solution. This solution was added ata time to a solution of benzhydryl7-amino-3-vinyl-3-cephem-4-carboxylate (2.72 g) andtrimethylsilylacetamide (5.5 g) in methylene chloride at -20° C. withstirring, and the stirring was continued at -20° to -10° C. for an hour.To the reaction mixture were added water (50 ml) and ethyl acetate (200ml), and the separated organic layer was washed with 5% aqueous sodiumbicarbonate and then a saturated aqueous sodium chloride, followed bydrying over magnesium sulfate. Removal of the solvent gave benzhydryl7-[2-(tert-butoxycarbonylmethoxyimino)-2-(6-formamidopyridin-2-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (4.8 g), mp 154°-157° C.

IR (Nujol): 3240, 1777, 1745, 1715, 1689, 1667 cm⁻¹.

NMR δppm (DMSO-d₆): 1.40 (9H, s), 3.50, 3.93 (2H, ABq, J=18 Hz), 4.60(2H, s), 5.20 (1H, d, J=11 Hz), 5.25 (1H, d, J=5 Hz), 5.56 (1H, d, J=18Hz), 5.95 (1H, dd, J=5 Hz, 8 Hz), 6.9 (1H, m), 6.9 (1H, s), 7.3 (10H,m), 7.3-8.3 (3H, m), 9.4 (1H, broad s), 9.53 (1H, d, J=8 Hz), 10.6 (1H,d, J=6 Hz).

EXAMPLE 205

Benzhydryl7-[2-(trans-3-tert-butoxycarbonylallyloxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (4.83 g) was obtained by reacting benzhydryl7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (3.0 g) with2-(trans-3-tert-butoxycarbonylallyloxyimino)-2-(2-formamidothiazol-4-yl)aceticacid (syn isomer) (2.7 g) according to similar manners to those ofExamples 202 to 204.

IR (Nujol): 3250, 1780, 1710, 1660 cm⁻¹.

NMR δppm (DMSO-d₆): 1.47 (9H, s), 3.79 (2H, q, J=18.0 Hz), 4.89 (2H, m),5.34 (1H, d, J=11.0 Hz), 5.35 (1H, d, J=5.0 Hz), 5.68 (1H, d, J=18.0Hz), 5.86-6.30 (2H, m), 6.52-7.22 (2H, m), 7.00 (1H, s), 7.21-7.74 (11H,m), 8.58 (1H, s), 9.91 (1H, d, J=8.0 Hz), 12.73 (1H, broad s).

EXAMPLE 206

Benzhydryl7-[2-cyanomethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (3.1 g) was obtained by reacting benzhydryl7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (2.5 g) with2-cyanomethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer)(1.6 g) according to similar manners to those of Examples 202 to 204.

IR (Nujol): 3180, 1770, 1720, 1680 cm⁻¹.

NMR δppm (DMSO-d₆): 3.77 (2H, m), 5.03-6.10 (5H, m), 5.81 (1H, dd, J=5.0Hz, 8.0 Hz), 6.43-7.13 (1H, m), 6.96 (1H, s), 7.35 (10H, s), 7.56 (1H,s), 8.53 (1H, s), 9.93 (1H, d, J=8.0 Hz).

EXAMPLE 207

Benzhydryl7-[2-tert-butoxycarbonylmethoxyimino-2-(5-chloro-2-formamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (5.6 g) was obtained by reacting benzhydryl7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (3.43 g) with2-tert-butoxycarbonylmethoxyimino-2-(5-chloro-2-formamidothiazol-4-yl)aceticacid (syn isomer) (3.2 g) according to similar manners to those ofExamples 202 to 204.

IR (Nujol): 3200, 1780, 1720, 1680, 1606, 1540 cm⁻¹.

NMR δppm (DMSO-d₆): 1.43 (9H, s), 3.77 (2H, m), 4.67 (2H, s), 5.30 (1H,d, J=5 Hz), 5.32 (1H, d, J=11 Hz), 5.65 (1H, d, J=18 Hz), 6.03 (1H, dd,J=5 Hz, 8 Hz), 6.83 (1H, dd, J=11 Hz, 18 Hz), 7.02 (1H, s), 7.23-7.8(10H, m), 8.60 (1H, s), 9.73 (1H, d, J=8 Hz).

EXAMPLE 208

Benzhydryl7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (5.7 g), mp 154°-159° C., was obtained by reactingbenzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate (3.8 g) with2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetic acid (syn isomer) (3.0g) according to similar manners to those of Examples 202 to 204.

IR (Nujol): 3350, 1770, 1720, 1670, 1613 cm⁻¹.

NMR δppm (DMSO-d₆): 3.78 (2H, m), 4.0 (3H, s), 5.30 (1H, d, J=11 Hz),5.33 (1H, d, J=5 Hz), 5.63 (1H, d, J=18 Hz), 6.03 (1H, dd, J=5 Hz, 8Hz), 6.83 (1H, dd, J=11 Hz, 18 Hz), 7.0 (1H, s), 7.4 (10H, m), 7.0-8.0(3H, m), 9.3 (1H, broad s), 9.7 (1H, d, J=8 Hz), 10.7 (1H, d, J=5 Hz).

The following compounds were obtained by reacting7-amino-3-vinylcephalosporanic acid derivatives with the correspondingacylating agents according to similar manners to those of Examples 202to 204.

EXAMPLE 209

Benzhydryl7-[2-(2-aminothiazol-4-yl)-2-(3-tert-butoxycarbonylpropoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 3340, 3250, 1780, 1720, 1680, 1620 cm⁻¹.

EXAMPLE 210

Benzhydryl7-[2-(2-aminothiazol-4-yl)-2-(trans-3-tert-butoxycarbonylallyloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 3250, 1770, 1700, 1670, 1610 cm⁻¹.

EXAMPLE 211

Benzhydryl7-[2-(6-aminopyridin-2-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 3350, 1778, 1721, 1682, 1615 cm⁻¹.

EXAMPLE 212

Benzhydryl7-[2-(2-aminothiazol-4-yl)-2-cyanomethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 3430, 3250, 1780, 1720, 1680, 1660 cm⁻¹

EXAMPLE 213

Benzhydryl7-[2-(2-amino-5-chlorothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 3425, 3270, 1780, 1720, 1675, 1620, 1540 cm⁻¹.

EXAMPLE 214

Benzhydryl7-[2-(6-aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 3250, 1775, 1720 (shoulder), 1680 (broad) cm⁻¹.

EXAMPLE 215

7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3350, 3250, 1770, 1670, 1620, 1530 cm⁻¹.

EXAMPLE 216

7-[2-(2-Aminothiazol-4-yl)-2-cyanomethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3330, 2020, 1770, 1670, 1620 cm⁻¹

EXAMPLE 217

7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3350, 3250, 1780 (broad), 1667 (broad) cm⁻¹.

EXAMPLE 218

Pivaloyloxymethyl7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 3400-3100, 1770, 1760, 1680, 1620, 1530 cm⁻¹.

EXAMPLE 219

Phosphorus oxychloride (4.1 g) was added to a suspension of2-(5-amino-1,2,4-thiadiazol-3-yl)-2-tert-butoxycarbonylmethoxyiminoaceticacid (syn isomer) (2.0 g) in methylene chloride (26 ml), and the mixturewas stirred at ambient temperature for 1.5 hours. Thereto was addedN,N-dimethylformamide (4.0 ml) at -15° C., followed by stirring at -15°to -5° C. for 40 minutes to prepare the activated acid solution.

On the other hand, trimethylsilylacetamide (5.5 g) was added to asuspension of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylatehydrochloride (2.6 g) in methylene chloride (26 ml), and the mixture wasstirred at 35° to 40° C. for 10 minutes.

To this solution was added at a time the activated acid solutionprepared before at -10° C., and the mixture was stirred at -10° to -5°C. for half an hour. To the reaction mixture were added a saturatedaqueous sodium chloride (150 ml) and ethyl acetate (150 ml), followed byadjusting to pH 7.5 with a saturated aqueous sodium bicarbonate. Theseparated organic layer was washed with a saturated aqueous sodiumchloride and then dried over magnesium sulfate. Removal of the solventgave benzhydryl7-[2-[5-{N-(N,N-dimethylaminomethylene)-amino}-1,2,4-thiadiazol-3-yl]-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (4.13 g).

IR (Nujol): 1770, 1710, 1620 cm⁻¹.

NMR δppm (DMSO-d₆): 1.47 (9H, s), 3.09 (3H, s), 3.20 (3H, s), 3.82 (2H,m), 4.71 (2H, s), 5.17-6.17 (3H, m), 5.32 (1H, d, J=5.0 Hz), 6.80 (1H,dd, J=12.0 Hz, 18.0 Hz), 7.00 (1H, s), 7.43 (10H, s), 8.50 (1H, s), 9.69(1H, d, J=8.0 Hz).

EXAMPLE 220

To a solution of benzhydryl7-[2-tert-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (2.5 g) in anisole (2.5 ml) and methylene chloride (5.0 ml)was added trifluoroacetic acid (10.0 ml) under ice-cooling, and themixture was stirred at ambient temperature for 2 hours. To the reactionmixture was added dropwise diisopropyl ether, and the precipitatedcrystals were collected by filtration, washed with diisopropyl ether toobtain7-[2-carboxymethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (1.57 g).

IR (Nujol): 3130, 1770, 1670 cm⁻¹.

NMR δppm (DMSO-d₆): 3.71 (2H, q, J=18.0 Hz), 4.66 (2H, s), 5.22 (1H, d,J=4.0 Hz), 5.22-5.85 (2H, m), 5.84 (1H, dd, J=4.0 Hz, 8.0 Hz), 6.93 (1H,dd, J=12.0 Hz, 18.0 Hz), 7.44 (1H, s), 8.50 (1H, s), 9.59 (1H, d, J=8.0Hz), 12.30 (1H, broad s).

EXAMPLE 221

To a solution of benzhydryl7-[2-(2-aminothiazol-4-yl)-2-(trans-3-tert-butoxycarbonylallyloxyimino)-acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (4.4 g) and anisole (4.4 ml) in methylene chloride (9.0 ml)was added trifluoroacetic acid (17.6 ml) under ice-cooling, and themixture was stirred at ambient temperature for 2 hours. To the reactionmixture was added diisopropyl ether, and the precipitated substance wascollected by filtration, which was washed with diisopropyl ether. Tothis substance were added ethyl acetate and water, and then adjusted topH 7.5 with a saturated aqueous sodium bicarbonate. The separatedaqueous layer was washed with ethyl acetate, and the remaining ethylacetate in the aqueous solution was completely removed by evaporation,followed by adjusting to pH 2.2 with 10% hydrochloric acid. Theprecipitated substance was collected by filtration and then dried toobtain7-[2-(2-aminothiazol-4-yl)-2-(trans-3-carboxyallyloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (2.31 g).

IR (Nujol): 3250, 1760, 1690, 1650 cm⁻¹.

NMR δppm (DMSO-d₆): 3.73 (2H, q, J=16.0 Hz), 4.84 (2H, m), 5.24 (1H, d,J=4.0 Hz), 5.34 (1H, d, J=12.0 Hz), 5.47-6.23 (3H, m), 6.63-7.34 (2H,m), 6.83 (1H, s), 9.77 (1H, d, J=8.0 Hz).

EXAMPLE 222

A mixture of benzhydryl7-[2-(6-aminopyridin-2-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (6.0 g), anisole (10 ml) and trifluoroacetic acid (60 ml)was stirred at ambient temperature for an hour. The reaction mixture waspoured into diisopropyl ether (600 ml) with stirring, and theprecipitated substance was collected by filtration, washed withdiisopropyl ether and then dissolved in water (100 ml), followed byadjusting to pH 7.5 with 5% aqueous sodium bicarbonate and washing withethyl acetate (50 ml). The resultant aqueous solution was adjusted to pH2.5 with conc. hydrochloric acid, and extracted with ethyl acetate (200ml) and tetrahydrofuran (200 ml). The remaining aqueous solution wasfurther adjusted to pH 1.5 with conc. hydrochloric acid and extractedwith tetrahydrofuran (100 ml). The combined extracts were washed with asaturated aqueous sodium chloride and then dried over magnesium sulfate.Removal of the solvent gave a residue, which was washed with acetone anddiisopropyl ether to obtain7-[2-(6-aminopyridin-2-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (2.4 g), mp 173°-178° C. (dec.).

IR (Nujol): 3300, 1763 (broad), 1660 (broad) cm⁻¹.

NMR δppm (DMSO-d₆): 3.68 (2H, m), 4.77 (2H, broad s), 5.25 (1H, d, J=5Hz), 5.30 (1H, d, J=11 Hz), 5.87 (1H, d, J=18 Hz), 5.83 (1H, dd, J=5 Hz,8 Hz), 6.5-8.0 (3H, m), 9.7 (1H, d, J=8 Hz).

EXAMPLE 223

7-[2-(2-Aminothiazol-4-yl)-2-(3-carboxypropoxyimino)-acetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (1.75 g) was obtained by reacting benzhydryl7-[2-(2-aminothiazol-4-yl)-2-(3-tert-butoxycarbonylpropoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (3.2 g) with trifluoroacetic acid (12.8 ml) in the presenceof anisole (3.2 ml) according to similar manners to those of Examples220 to 222.

IR (Nujol): 3300, 1760, 1660 cm⁻¹.

NMR δppm (DMSO-d₆): 1.95 (2H, m), 2.37 (2H, t, J=6.0 Hz), 3.73 (2H, q,J=17.0 Hz), 4.13 (2H, t, J=6.0 Hz), 5.23 (1H, d, J=5.0 Hz), 5.23-6.00(3H, m), 6.79 (1H, s), 7.00 (1H, dd, J=11.0 Hz, 18.0 Hz), 9.65 (1H, d,J=8.0 Hz).

EXAMPLE 224

7-[2-(2-Amino-5-chlorothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (2.2 g) was obtained by reacting benzhydryl7-[2-(2-amino-5-chlorothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (4.6 g) with trifluoroacetic acid (14.4 g) in the presenceof anisole (2.7 g) according to similar manners to those of Examples 220to 222.

IR (Nujol): 3400, 3180, 1770, 1685, 1650, 1610 cm⁻¹

NMR δppm (DMSO-d₆): 3.70 (2H, q, J=18 Hz), 4.63 (2H, s), 5.18 (1H, d,J=5 Hz), 5.33 (1H, d, J=11 Hz), 5.56 (1H, d, J=18 Hz), 5.83 (1H, dd, J=5Hz, 8 Hz), 6.95 (1H, dd, J=11 Hz, 18 Hz), 9.45 (1H, d, J=8 Hz).

EXAMPLE 225

Trifluoroacetic acid (16.0 ml) was added to a solution of benzhydryl7-[2-[5-{N-(N,N-dimethylaminomethylene)amino}-1,2,4-thiadiazol-3-yl]-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (4.0 g) in methylene chloride (8.0 ml) and anisole (4.0 ml)under ice-cooling, and the mixture was stirred at ambient temperaturefor 1.5 hours. The reaction mixture was added dropwise to diisopropylether (200 ml), and the precipitated substance was collected byfiltration and then added to a mixture of water and ethyl acetate,followed by adjusting to pH 7.5 with a saturated aqueous sodiumbicarbonate. The separated aqueous layer was saturated with sodiumchloride and adjusted to pH 2.5 with 10% hydrochloric acid, followed byextraction with a mixed solvent of ethyl acetate and tetrahydrofuran(1:2 by volume). The extract was washed with a saturated aqueous sodiumchloride and then dried over magnesium sulfate. Removal of the solventgave a residue, which was washed with diethyl ether and collected byfiltration to obtain7-[2-(5-formamido-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (1.75 g).

IR (Nujol): 3200, 1770, 1670 cm⁻¹.

NMR δppm (DMSO-d₆): 3.70 (2H, m), 4.75 (2H, s), 5.24 (1H, d, J=5.0 Hz),5.33 (1H, d, J=12.0 Hz), 5.61 (1H, d, J=18.0 Hz), 5.91 (1H, dd, J=5.0Hz, 8.0 Hz), 6.96 (1H, dd, J=12.0 Hz, 18 Hz), 8.87 (1H, s), 9.70 (1H, d,J=8.0 Hz), 13.47 (1H, broad s).

EXAMPLE 226

To a solution of benzhydryl7-[2-tert-butoxycarbonylmethoxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (2 g) and anisole (8.0 ml) in dioxane (8 ml) and tert-butylalcohol (8.0 ml) was added p-toluenesulfonic acid (2.2 g), followed bystirring at 60° C. for 5 hours. To the reaction mixture were added ethylacetate and water, and then adjusted to pH 7.5 with a saturated aqueoussodium bicarbonate. The aqueous layer was separated and washed withethyl acetate, and thereto were added ethyl acetate and tetrahydrofuran,followed by adjusting to pH 2.2 with 10% hydrochloric acid. After theaqueous layer was saturated with sodium chloride, the organic layer wasseparated, washed with a saturated aqueous sodium chloride and thendried over magnesium sulfate. Removal of the solvent gave a residue,which was pulverized with diisopropyl ether and collected by filtration.To this substance was added water and then adjusted to pH 5.5 with 2Naqueous sodium hydroxide. The aqueous solution was subjected to columnchromatography on a nonionic adsorption resin, "Diaion HP-20" (20 ml),and elution was carried out with water (40 ml). To the eluate were addedethyl acetate and tetrahydrofuran, followed by adjusting the pH 2.2 with10% hydrochloric acid. After the aqueous layer was saturated with sodiumchloride, the organic layer was separated, washed out with a saturatedaqueous sodium chloride and then dried over magnesium sulfate. Removalof the solvent gave a residue, which was pulverized with diisopropylether and collected by filtration to obtain7-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (0.31 g).

IR (Nujol): 3350, 1770, 1680, 1640 cm⁻¹.

NMR δppm (DMSO-d₆): 3.70 (2H, q, J=18 Hz), 4.62 (2H, s), 5.21 (1H, d,J=5 Hz), 5.82 (1H, dd, J=5 Hz, 8 Hz), 5-6 (2H, m), 6.82 (1H, s), 7.22(2H, broad s), 6.5-7.5 (1H, m), 9.5 (1H, d, J=8 Hz).

The following compounds were obtained by reacting7-acylamino-3-vinylcephalosporanic acid derivatives having a formamidogroup, a tert-butoxycarbonyl group and a benzhydryl ester withp-toluenesulfonic acid in the presence of anisole according to a similarmanner to that of Example 226.

EXAMPLE 227

7-[2-(2-Aminothiazol-4-yl)-2-(trans-3-carboxyallyloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3250, 1760, 1690, 1650 cm⁻¹.

EXAMPLE 228

7-[2-(6-Aminopyridin-2-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3300, 1763 (broad), 1660 (broad) cm⁻¹.

EXAMPLE 229

7-[2-(2-Aminothiazol-4-yl)-2-(3-carboxypropoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3300, 1760, 1660 cm⁻¹.

EXAMPLE 230

7-[2-(2-Amino-5-chlorothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3400, 3180, 1770, 1685, 1650, 1610 cm⁻¹.

EXAMPLE 231

A mixture of benzhydryl7-[2-(3-tert-butoxycarbonylpropoxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (3.5 g), conc. hydrochloric acid (1.0 g), methanol (30 ml)and tetrahydrofuran (15.0 ml) was stirred at ambient temperature for 2.5hours. To the reaction mixture was added ethyl acetate, followed byadjusting to pH 7.5 with a saturated aqueous sodium bicarbonate. Theseparated organic layer was washed with a saturated aqueous sodiumchloride and then dried over magnesium sulfate. Removal of the solventgave a residue, which was pulverized with diisopropyl ether to obtainbenzhydryl7-[2-(3-tert-butoxycarbonylpropoxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (3.33 g).

IR (Nujol): 3340, 3250, 1780, 1720, 1680, 1620 cm⁻¹.

NMR δppm (DMSO-d₆): 1.40 (9H, s), 1.87 (2H, m), 2.35 (2H, t, J=7.0 Hz),3.76 (2H, m), 4.11 (2H, t, J=7.0 Hz), 5.30 (1H, d, J=5.0 Hz), 5.32 (1H,d, J=12.0 Hz), 5.66 (1H, d, J=18.0 Hz), 5.91 (1H, dd, J=5.0 Hz, 8.0 Hz),6.78 (1H, s), 6.79 (1H, dd, J=12.0 Hz, 18.0 Hz), 6.98 (1H, s), 7.39(10H, s), 9.66 (1H, d, J=8.0 Hz).

EXAMPLE 232

A mixture of benzhydryl7-[2-(trans-3-tert-butoxycarbonylallyloxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (4.7 g), conc. hydrochloric acid (1.34 g), methanol (30 ml)and tetrahydrofuran (10 ml) was stirred at ambient temperature for 2.5hours. To the reaction mixture was added ethyl acetate, followed byadjusting to pH 7.5 with a saturated aqueous sodium bicarbonate. Theseparated organic layer was washed with a saturated aqueous sodiumchloride and then dried over magnesium sulfate. Removal of the solventgave a residue, which was pulverized with diisopropyl ether to obtainbenzhydryl7-[2-(trans-3-tert-butoxycarbonylallyloxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (4.50 g).

IR (Nujol): 3250, 1770, 1700, 1670, 1610 cm⁻¹.

NMR δppm (DMSO-d₆): 1.45 (9H, s), 3.76 (2H, m), 4.86 (2H, m), 5.34 (1H,d, J=12.0 Hz), 5.35 (1H, d, J=5.0 Hz), 5.68 (1H, d, J=18.0 Hz),5.77-6.30 (2H, m), 6.54-7.17 (2H, m), 6.86 (1H, s), 7.00 (1H, s),7.17-7.70 (10H, m), 9.81 (1H, d, J=8.0 Hz).

EXAMPLE 233

To a suspension of benzhydryl7-[2-(6-formamidopyridin-2-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (4.8 g) in methanol (300 ml) was added conc. hydrochloricacid (2.88 ml), and the mixture was stirred at 35° C. for an hour. Thereaction mixture was adjusted to pH 5.5 with 5% aqueous sodiumbicarbonate, and the methanol was removed by distillation under reducedpressure, followed by extraction with ethyl acetate (300 ml). Theextract was washed with a saturated aqueous sodium chloride and thendried over magnesium sulfate. Removal of the solvent gave benzhydryl7-[2-(6-aminopyridin-2-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (4.5 g), mp 125°-129° C.

IR (Nujol): 3350, 1778, 1721, 1682, 1615 cm⁻¹.

NMR δppm (DMSO-d₆): 1.45 (9H, s), 3.55, 3.97 (2H, ABq, J=18 Hz), 4.65(2H, broad s), 5.29 (1H, d, J=5 Hz), 5.29 (1H, d, J=11 Hz), 5.95 (1H, d,J=18 Hz), 5.98 (1H, dd, J=5 Hz, 8 Hz), 6.9 (1H, m), 6.97 (1H, s),6.8-7.7 (3H, m), 7.4 (10H, m), 9.47 (1H, d, J=8 Hz).

EXAMPLE 234

Benzhydryl7-[2-(2-aminothiazol-4-yl)-2-cyanomethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (2.17 g) was obtained by reacting benzhydryl7-[2-(2-formamidothiazol-4-yl)-2-cyanomethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (3.0 g) with conc. hydrochloric acid (0.35 g) according tosimilar manners to those of Examples 231 to 233.

IR (Nujol): 3430, 3250, 1780, 1720, 1680, 1660 cm⁻¹

NMR δppm (DMSO-d₆): 3.77 (2H, m), 5.02 (2H, s), 5.10-6.08 (2H, m), 5.28(1H, d, J=5.0 Hz), 5.85 (1H, dd, J=5.0 Hz, 8.0 Hz), 6.83 (1H, dd, J=10.0Hz, 18.0 Hz), 6.89 (1H, s), 6.95 (1H, s), 7.09-7.63 (10H, m), 9.83 (1H,d, J=8.0 Hz).

EXAMPLE 235

Benzhydryl7-[2-(2-amino-5-chlorothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (4.6 g) was obtained by reacting benzhydryl7-[2-(2-formamido-5-chlorothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (5.5 g) with conc. hydrochloric acid (2.3 ml) according tosimilar manners to those of Examples 231 to 233.

IR (Nujol): 3425, 3270, 1780, 1720, 1675, 1620, 1540 cm⁻¹.

NMR δppm (DMSO-d₆): 1.43 (9H, s), 3.77 (2H, m), 4.63 (2H, s), 5.30 (1H,d, J=5 Hz), 5.32 (1H, d, J=11 Hz), 5.68 (1H, d, J=17 Hz), 6.00 (1H, dd,J=5 Hz, 8 Hz), 6.85 (1H, dd, J=11 Hz, 17 Hz), 7.03 (1H, s), 7.22-7.90(10H, m), 9.60 (1H, d, J=8 Hz).

EXAMPLE 236

Benzhydryl7-[2-(6-aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (4.5 g), mp 183°-188° C., was obtained by reactingbenzhydryl7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (5.7 g) with conc. hydrochloric acid (4.3 ml) according tosimilar manners to those of Examples 231 to 233.

IR (Nujol): 3250, 1775, 1720 (shoulder), 1680 (broad) cm⁻¹.

NMR δppm (DMSO-d₆): 3.8 (2H, m), 3.93 (3H, s), 5.3 (1H, d, J=5 Hz), 5.3(1H, d, J=11 Hz), 5.63 (1H, d, J=18 Hz), 5.95 (1H, dd, J=11 Hz, 18 Hz),6.5-8.2 (3H, m), 6.9 (1H, m), 7.0 (1H, s), 7.4 (10H, m), 9.57 (1H, d,J=8 Hz).

The following compounds were obtained by reacting7-acylamino-3-vinylcephalosporanic acid derivatives having a formamidogroup with conc. hydrochloric acid according to similar manners to thoseof Examples 231 to 233.

EXAMPLE 237

Benzhydryl7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 3300, 3175, 1770, 1720, 1670, 1610, 1510 cm⁻¹.

EXAMPLE 238

7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3350, 3250, 1770, 1670, 1620, 1530 cm⁻¹.

EXAMPLE 239

7-[2-(2-Aminothiazol-4-yl)-2-cyanomethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3330, 2020, 1770, 1670, 1620 cm⁻¹.

EXAMPLE 240

7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3350, 3250, 1780 (broad), 1667 (broad) cm⁻¹.

EXAMPLE 241

7-[2-(2-Aminothiazol-4-yl)-2-(trans-3-carboxyallyloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3250, 1760, 1690, 1650 cm⁻¹.

EXAMPLE 242

7-[2-(6-Aminopyridin-2-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3300, 1763 (broad), 1660 (broad) cm⁻¹.

EXAMPLE 243

7-[2-(2-Aminothiazol-4-yl)-2-(3-carboxypropoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3300, 1760, 1660 cm⁻¹.

EXAMPLE 244

7-[2-(2-Amino-5-chlorothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3400, 3180, 1770, 1685, 1650, 1610 cm⁻¹.

EXAMPLE 245

Pivaloyloxymethyl7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 3400-3100, 1770, 1760, 1680, 1620 1530 cm⁻¹.

EXAMPLE 246

To a suspension of benzhydryl7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (6.2 g) in methylene chloride (60 ml) were added anisole(9.3 g) and trifluoroacetic acid (24.5 g), and the mixture was stirredat ambient temperature for 1.5 hours. After removal of the solvent, theresidue was added dropwise to diisopropyl ether (600 ml), and theprecipitated substance was collected by filtration. This substance wassuspended in water (50 ml) and then adjusted to pH 7.5 with 2N aqueoussodium hydroxide, followed by washing twice with a mixture of ethylacetate (50 ml) and tetrahydrofuran (50 ml). To the resultant aqueoussolution were added ethyl acetate (50 ml) and tetrahydrofuran (50 ml),and the mixture was saturated with sodium chloride and adjusted to pH1.0 with 10% hydrochloric acid. The organic layer was separated, and theremaining aqueous solution was extracted twice with a mixture of ethylacetate and tetrahydrofuran. The combined organic solution was washedwith an aqueous sodium chloride and then dried over magnesium sulfate.Removal of the solvent gave a residue, which was pulverized with diethylether to obtain7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (3.9 g).

IR (Nujol): 3350, 3250, 1770, 1670, 1620, 1530 cm⁻¹.

NMR δppm (DMSO-d₆): 3.71 (2H, m), 3.93 (3H, s), 5.18 (1H, d, J=5 Hz),5.32 (1H, d, J=11 Hz), 5.55 (1H, d, J=17 Hz), 5.82 (1H, dd, J=5 Hz, 8Hz), 6.95 (1H, dd, J=11 Hz, 17 Hz), 9.58 (1H, d, J=8 Hz).

EXAMPLE 247

7-[2-(2-Aminothiazol-4-yl)-2-cyanomethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (0.92 g) was obtained by reacting benzhydryl7-[2-(2-aminothiazol-4-yl)-2-cyanomethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (2.1 g) with trifluoroacetic acid (8.4 ml) in the presenceof anisole (2.1 ml) according to a similar manner to that of Example246.

IR (Nujol): 3330, 2020, 1770, 1670, 1620 cm⁻¹.

NMR δppm (DMSO-d₆): 3.73 (2H, q, J-18.0 Hz), 5.02 (2H, s), 5.23 (1H, d,J=5.0 Hz), 5.34 (1H, d, J=12.0 Hz), 5.37-6.80 (1H, m), 5.79 (1H, dd,J=5.0 Hz, 8.0 Hz), 6.63-7.38 (1H, m), 6.91 (1H, s), 9.83 (1H, d, J=8.0Hz).

EXAMPLE 248

7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (0.85 g), mp 183°-188° C. (dec.), was obtained byreacting benzhydryl7-[2-(6-aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (4.5 g) with trifluoroacetic acid (15 ml) in the presenceof anisole (5 ml) according to a similar manner to that of Example 246.

IR (Nujol): 3350, 3250, 1780 (broad), 1667 (broad) cm⁻¹.

NMR δppm (DMSO-d₆): 3.58, 3.97 (2H, ABq, J=18 Hz), 4.12 (3H, s), 5.28(1H, d, J=5 Hz), 5.36 (1H, d, J=11 Hz), 5.62 (1H, d, J=18 Hz), 5.87 (1H,dd, J=5 Hz, 8 Hz), 6.7-8.2 (6H, m), 9.93 (1H, d, J=8 Hz).

EXAMPLE 249

To a suspension of7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (2.3 g) in water (30 ml) was added sodium bicarbonate(0.47 g), and the mixture was stirred for a while. The insolublesubstance was removed by filtration, and then the filtrate waslyophilized to prepare sodium salt of the above compound (2.0 g).

This product was dissolved in N,N-dimethylformamide (20 ml), and theretowas added dropwise a solution of iodomethyl pivalate (1.23 g) inN,N-dimethylformamide (3 ml) under ice-cooling, followed by stirringbelow 5° C. for 10 minutes. To the reaction mixture were added ethylacetate (50 ml) and water (50 ml), and the organic layer was separated,and washed three times with a saturated aqueous sodium bicarbonate (30ml) and three times with an aqueous sodium chloride (30 ml), followed bydrying over magnesium sulfate. Removal of the solvent gave a residue,which was pulverized with diisopropyl ether to obtain pivaloyloxymethyl7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (1.4 g), mp 125°-133° C. (dec.).

IR (Nujol): 3400-3100, 1770, 1760, 1680, 1620, 1530 cm⁻¹.

NMR δppm (DMSO-d₆): 1.15 (9H, s), 3.77 (2H, q, J=17 Hz), 3.93 (3H, s),5.23 (1H, d, J=5 Hz), 5.38 (1H, d, J=11 Hz), 5.7 (1H, d, J=17 Hz),5.7-6.1 (3H, m), 6.85 (1H, dd, J=11 Hz, 17 Hz), 8.15 (2H, broad s), 9.67(1H, d, J=8 Hz).

EXAMPLE 250

2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-tert-butoxycarbonylmethoxyimino)aceticacid (syn isomer) (2.5 g) was added to a solution of phosphoruspentachloride (1.7 g) in methylene chloride at -18° C., followed bystirring at -5° to -15° C. for an hour. After dried diisopropyl ether(75 ml) was added thereto at -10° to -5° C., the mixture was stirred atambient temperature for 10 minutes. The precipitates were collected byfiltration and then washed with diisopropyl ether.

On the other hand, trimethylsilylacetamide (5.8 g) was added to asuspension of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylatehydrochloride (2.7 g) in methylene chloride (27 ml), followed bystirring for a while. To this solution was added the precipitatesobtained above at -10° C., and the mixture was stirred at the sametemperature for half an hour. To the reaction mixture were added water(80 ml) and ethyl acetate (200 ml), followed by separation of theorganic layer. Thereto was added water, and the mixture was adjusted topH 7.5 with a saturated aqueous sodium bicarbonate. The separatedorganic layer was washed with a saturated aqueous sodium chloride andthen dried over magnesium sulfate. Removal of the solvent gavebenzhydryl7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3cephem-4-carboxylate (syn isomer) (3.53 g).

IR (Nujol): 3400, 1770, 1720, 1670, 1620 cm⁻¹.

NMR δppm (DMSO-d₆): 1.46 (9H, s), 3.77 (2H, q, J=19.0 Hz), 4.67 (2H, s),5.30 (1H, d, J=5.0 Hz), 5.33 (1H, d, J=11.0 Hz), 5.66 (1H, d, J=17.0Hz), 5.96 (1H, dd, J=5.0 Hz, 9.0 Hz), 6.80 (1H, dd, J=11.0 Hz, 17.0 Hz),6.99 (1H, s), 7.43 (10H, s), 8.23 (2H, broad s), 9.63 (1H, d, J=9.0 Hz).

EXAMPLE 251

To a suspension of2-(4-aminopyrimidin-2-yl)-2-tert-butoxycarbonylmethoxyiminoacetic acid(syn isomer) (1.3 g) in ethyl acetate (25 ml) was added phosphorusoxychloride (0.5 ml) under ice-cooling with stirring, followed bystirring at 0° to 5° C. for half an hour. After trimethylsilylacetamide(28 mg) was added thereto, the mixture was stirred at the sametemperature for half an hour. To the mixture was added phosphorusoxychloride (0.5 ml) at 0° to 5° C., followed by stirring at the sametemperature for 15 minutes. Thereto was added N,N-dimethylformamide(0.37 ml) at 0° to 5° C., followed by stirring under ice-cooling forhalf an hour to prepare the activated acid solution. This solution wasadded at a time to a solution of benzhydryl7-amino-3-vinyl-3-cephem-4-carboxylate (1.32 g) andtrimethylsilylacetamide (3.5 g) in methylene chloride (30 ml) at -20°C., followed by stirring at -10° C. for 40 minutes. The reaction mixturewas poured into ethyl acetate, and the separated organic layer waswashed with 5% aqueous sodium bicarbonate and 5% aqueous sodiumchloride, followed by drying over magnesium sulfate. After removal ofthe solvent, the residual oil was subjected to column chromatography onsilica gel (100 ml) using a mixed solvent of diisopropyl ether and ethylacetate as an eluent. The fractions containing a desired compound werecollected and then evaporated to obtain benzhydryl7-[2-(4-aminopyrimidin-2-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (0.4 g), mp 155° to 158° C.

IR (Nujol): 3250, 1780, 1723, 1690, 1628 cm⁻¹.

NMR δppm (CDCl₃): 1.46 (9H, s), 3.44, 3.66 (2H, ABq, J=18 Hz), 4.78 (2H,s), 5.12 (1H, d, J=5 Hz), 5.27 (1H, d, J=11 Hz), 5.40 (1H, d, J=18 Hz),6.10 (1H, dd, J=5 Hz, 8 Hz), 6.67 (1H, d, J=6 Hz), 6.96 (1H, s), 6.98(1H, dd, J=11 Hz, 18 Hz), 7.3 (10H, m), 8.28 (1H, d, J=6 Hz), 8.50 (1H,d, J=8 Hz).

EXAMPLE 252

Benzhydryl7-[2-(O,O-diethylphosphonomethyoxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (4.3 g), mp 135° to 142° C., was obtained by reactingbenzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate (4.7 g) with anactivated acid solution, which was prepared from2-(O,O-diethylphosphonomethoxyimino)-2-(2-formamidothiazol-4-yl)aceticacid (syn isomer) (5.5 g), phosphorus oxychloride (2.07 ml) andN,N-dimethylformamide (1.75 ml) in tetrahydrofuran (55 ml) in aconventional manner, according to similar manners to those of Examples250 and 251.

IR (Nujol): 3400, 3160, 1785, 1723, 1675 cm⁻¹.

NMR δppm (DMSO-d₆): 1.25 (6H, t, J=6 Hz), 3.73 (2H, m), 4.13 (4H, m),4.57 (2H, d, J=7 Hz), 5.28 (1H, d, J=5 Hz), 5.2-5.8 (2H, m), 5.90 (1H,m), 6.80 (1H, dd, J=11 Hz, 18 Hz), 6.95 (1H, s), 7.37 (10H, m), 7.47(1H, s), 8.53 (1H, s), 9.80 (1H, d, J=8 Hz), 12.7 (1H, broad s).

EXAMPLE 253

Trifluoroacetic acid (13.6 ml) was added to a solution of benzhydryl7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (3.4 g) in methylene chloride (7.0 ml) and anisole (3.4 ml)under ice-cooling, followed by stirring at ambient temperature for 1.5hours. The reaction mixture was added dropwise to diisopropyl ether (150ml), and the precipitates were collected by filtration and then added toa mixture of water and ethyl acetate. After adjusting to pH 7.5 with asaturated aqueous sodium bicarbonate, the aqueous layer was separatedand then adjusted to pH 2.0 with 10% hydrochloric acid. The precipitateswere collected by filtration, washed with cold water and then dried toobtain7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (1.39 g).

IR (Nujol): 3380, 3280, 1760, 1720, 1670 cm⁻¹

NMR δppm (DMSO-d₆): 3.73 (2H, q, J=18.5 Hz), 4.69 (2H, s), 5.21 (1H, d,J=5.0 Hz), 5.33 (1H, d, J=12.0 Hz), 5.60 (1H, d, J=18.0 Hz), 5.86 (1H,dd, J=5.0 Hz, 8.0 Hz), 6.98 (1H, dd, J=12.0 Hz, 18.0 Hz), 8.16 (2H,broad s), 9.56 (1H, d, J=18.0 Hz).

EXAMPLE 254

To a solution of benzhydryl7-[2-(O,O-diethylphosphonomethoxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (4.2 g) in methylene chloride (20 ml) and anisole (2 ml)was added trifluoroacetic acid (5 ml) under ice-cooling, followed bystirring at 10° C. for 1.5 hours. The reaction mixture was addeddropwise to diisopropyl ether (400 ml), and the precipitates werecollected by filtration and washed with diisopropyl ether, followed bydrying under reduced pressure to obtain7-[2-(O,O-diethylphosphonomethoxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (2.8 g), mp 173° to 176° C.

IR (Nujol): 3160, 1775 (broad), 1680 (broad) cm⁻¹.

NMR δppm (DMSO-d₆): 1.28 (6H, t, J=6 Hz), 3.76 (2H, m), 4.17 (4H, m),4.58 (2H, d, J=7 Hz), 5.23 (1H, d, J=5 Hz), 5.36 (1H, d, J=11 Hz), 5.63(1H, d, J=18 Hz), 5.87 (1H, dd, J=5 Hz, 8 Hz), 7.0 (1H, dd, J=11 Hz, 18Hz), 7.70 (1H, s), 8.56 (1H, s), 9.82 (1H, d, J=8 Hz), 12.7 (1H, broads).

EXAMPLE 255

To a solution of7-[2-(O,O-diethylphosphonomethoxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (1.725 g) in methylene chloride (26 ml) were addedbis(trimethylsilyl)acetamide (3.05 g) and trimethylsilyl iodide (3.0 g)at 25° to 28° C., followed by stirring at ambient temperature for 18hours. Removal of the solvent gave a residual oil, which was dissolvedin methanol (25 ml). After addition of conc. hydrochloric acid (2 ml),the mixture was stirred at 30° C. for 2 hours. Removal of the solventgave a residue, which was dissolved in water (50 ml) and adjusted to pH5.5 with 1N aqueous sodium hydroxide. This aqueous solution wassubjected to column chromatography on a nonionic adsorption resin"Diaion HP-20". After washing with water, elution was carried out with10% aqueous methanol. The eluates containing a desired compound werecollected and then lyophilized to obtain 7-[2-phosphonomethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (synisomer) (1.0 g), mp 185° C. (dec.).

IR (Nujol): 3300 (broad), 1780, 1658, 1600 cm⁻¹.

NMR δppm (D₂ O+NaHCO₃): 3.70 (2H, m), 4.32 (2H, d, J=8 Hz), 5.28 (1H, d,J=5 Hz), 5.43 (1H, d, J=18 Hz), 5.50 (1H, d, J=11 Hz), 5.83 (1H, d, J=5Hz), 6.93 (1H, dd, J=11 Hz, 18 Hz), 7.0 (1H, s).

The following compound was obtained by reacting7-acylamino-3-vinylcephalosporanic acid derivatives having a formamidogroup with conc. hydrochloric acid according to similar manners to thoseof Examples 231 to 233.

EXAMPLE 256

7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3380, 3280, 1760, 1730, 1670 cm⁻¹.

EXAMPLE 257

To a suspension of benzhydryl7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (0.9 g) in methylene chloride (10 ml) and anisole (0.66 g)was added trifluoroacetic acid (2.5 g) under ice-cooling, followed bystirring at ambient temperature for an hour. The reaction mixture wasadded dropwise to diisopropyl ether (100 ml), and the precipitates werecollected by filtration and suspended in a mixture of ethyl acetate andwater, followed by adjusting to pH 7 with a saturated aqueous sodiumbicarbonate. The separated aqueous solution was saturated with sodiumchloride, and thereto was added a mixed solvent of ethyl acetate andtetrahydrofuran (8:2 by volume). After adjusting to pH 3.2 with 10%hydrochloric acid, the organic layer was separated out, washed with asaturated aqueous sodium chloride and then dried over magnesium sulfate.Removal of the solvent gave a residue, which was washed with diisopropylether to obtain7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer (0.4 g).

IR (Nujol): 3400-3100, 1780, 1660, 1630, 1540 cm⁻¹.

NMR δppm (DMSO-d₆): 3.72 (2H, q, J=18 Hz), 3.87 (3H, s), 5.20 (1H, d,J=5 Hz), 5.33 (1H, d, J=11 Hz), 5.58 (1H, d, J=18 Hz), 5.78 (1H, dd, J=5Hz, 8 Hz), 6.77 (1H, s), 6.95 (1H, dd, J=11 Hz, 18 Hz), 9.62 (1H, d, J=8Hz).

EXAMPLE 258

Vilsmeier reagent was prepared from phosphorus oxychloride (1.8 g) andN,N-dimethylformamide (0.8 g) in ethyl acetate (3.2 ml) in aconventional manner.2-(2-Cyclopenten-1-yloxyimino)-2-(2-formamidothiazol-4-yl)acetic acid(syn isomer) (2.7 g) was added to the stirred suspension of Vilsmeierreagent in dry tetrahydrofuran (30 ml) under ice-cooling and stirred for30 min. at same temperature [Solution A]. Trimethylsilylacetamide (8.1g) was added to the stirred suspension of7-amino-3-vinyl-3-cephem-4-carboxylic acid (2.0 g) in ethyl acetate, andthe mixture was stirred for 10 minutes at 35° to 40°0 C. To the mixturewas added the solution A at a time at -10° C. and stirred at sametemperature for 0.5 hour. Water (40 ml) was added to the reactionmixture, and the separated organic layer was added to water. The mixturewas adjusted to pH 7.5 with a saturated aqueous sodium bicarbonate. Theseparated aqueous layer was adjusted to pH 2.0 with 10% hydrochloricacid and extracted with ethyl acetate. The extract was washed with asaturated aqueous sodium chloride, and dried over magnesium sulfate. Thesolvent was removed to give precipitates of7-[2-(2-cyclopenten-1-yloxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylic acid(syn isomer) (3.20 g).

IR (Nujol): 3200, 1780, 1680, 1650 cm⁻¹.

NMR δppm (DMSO-d₆): 1.79-2.78 (4H, m), 3.73 (2H, q, J=20.0 Hz), 5.22(1H, d, J=5.0 Hz), 5.33 (1H, d, J=12.0 Hz), 5.60 (1H, d, J=18.0 Hz),5.71-6.28 (4H, m), 6.96 (1H, dd, J=12.0 Hz, 18.0 Hz), 7.40 (1H, s), 8.53(1H, s), 9.63 (1H, d, J=8.0 Hz).

EXAMPLE 259

Benzhydryl7-[2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate(5.1 g) was obtained by reacting benzhydryl7-amino-3-vinyl-3-cephem-4-carboxylate monohydrochloride (3.17 g) withthe acid chloride prepared from2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetic acid (2.7 g) andphosphorus pentachloride (1.75 g) according to a similar manner to thatof Example 258.

IR (Nujol): 1760, 1710, 1670 cm⁻¹.

NMR δppm (DMSO-d₆): 3.35 (2H, m), 3.73 (2H, m), 5.18 (1H, d, J=5 Hz),5.27 (1H, d, J=11 Hz), 5.62 (1H, d, J=18 Hz), 5.72 (1H, dd, J=5 Hz, 8Hz), 6.77 (1H, dd, J=11 Hz, 18 Hz), 6.93 (1H, s), 7.3 (10H, s), 7.63(1H, d, J=8 Hz), 8.05 (1H, s).

EXAMPLE 260

To a suspension of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylatemonohydrochloride (2.15 g) in methylene chloride (100 ml) was added2,6-lutidine (0.54 g) under ice-cooling. To the resultant solution wereadded 2-(5-tritylamino-1,3,4-thiadiazol-2-yl)acetic acid (2.4 g),N,N-dicyclohexylcarbodiimide (1.03 g), tetrahydrofuran (200 ml) andN,N-dimethylformamide (60 ml), and the mixture was stirred at ambienttemperature for a day. Removal of the solvent gave a residue, to which amixed solvent of ethyl acetate, tetrahydrofuran and water was added. Theinsoluble substances were removed by filtration, and the filtrate waswashed with dilute hydrochloric acid, a saturated aqueous sodiumbicarbonate and an aqueous sodium chloride, followed by drying overmagnesium sulfate. Removal of the solvent gave a residue, which waswashed with diisopropyl ether to obtain benzhydryl7-[2-(5-tritylamino-1,3,4-thiadiazol-2-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate(2.6 g).

IR (Nujol): 3300-3150, 1780, 1720, 1660, 1620, 1510 cm⁻¹.

EXAMPLE 261

Benzhydryl7-[2-(5-tritylamino-2H-tetrazol-2-yl)-acetamido]-3-vinyl-3-cephem-4-carboxylate(4.4 g) was obtained by reacting benzhydryl7-amino-3-vinyl-3-cephem-4-carboxylate monohydrochloride (3.5 g) with2-(5-tritylamino-2H-tetrazol-2-yl)acetic acid (3.5 g) in the presence of2,6-lutidine (0.9 g) and N,N'-dicyclohexylcarbodiimide (1.7 g) accordingto a similar manner to that of Example 260.

IR (Nujol): 3325, 1780, 1710, 1620, 1560 cm⁻¹.

NMR δppm (DMSO-d₆): 3.78 (2H, m), 5.02-5.92 (6H, m), 6.78 (1H, dd, J=11Hz, 17 Hz), 6.97 (1H, s), 7.05-7.65 (25H, m), 9.33 (1H, d, J=8 Hz).

EXAMPLE 262

A mixture of7-[2-(2-cyclopenten-1-yloxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (3.1 g) in methanol (22 ml), tetrahydrofuran (10 ml)and conc. hydrochloric acid (1.3 g) was stirred for 2.5 hours at ambienttemperature. The reaction mixture was added to a mixture of water andethyl acetate, and adjusted to pH 7.5 with a saturated aqueous sodiumbicarbonate. The separated aqueous layer was adjusted to pH 3.0 with 10%hydrochloric acid. The precipitates were filtered off, washed with waterand dried over phosphorus pentoxide in vacuo to give7-[2-(2-cyclopenten-1-yloxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (2.7 g).

IR (Nujol): 3270, 1765, 1650 cm⁻¹.

NMR δppm (DMSO-d₆): 1.92-2.75 (4H, m), 3.73 (2H, q, J=18.0 Hz), 5.21(1H, d, J=5.0 Hz), 5.21-6.33 (6H, m), 6.80 (1H, s), 6.96 (1H, dd, J=11.0Hz), 18.0 Hz), 9.62 (1H, d, J=8.0 Hz).

EXAMPLE 263

To a suspension of benzhydryl7-[2-(5-tritylamino-1,3,4-thiadiazol-2-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate(2.6 g) in methylene chloride (30 ml) and anisole (2.1 g) was addedtrifluoroacetic acid (7.6 g) under ice-cooling, followed by stirring atambient temperature for 1.5 hours. The reaction mixture was poured intodiisopropyl ether (300 ml), and the precipitates were collected byfiltration and suspended in water (40 ml). After adjusting to pH 7 with10% aqueous sodium hydroxide, the aqueous solution was washed with ethylacetate and then adjusted to pH 5 with 10% hydrochloric acid. Theorganic solvent included in the resultant aqueous solution wascompletely removed by evaporation, and the resultant aqueous solutionwas adjusted to pH 4 with dilute acetic acid, which was chromatographedon a non-ionic adsorption resin "Diaion HP-20" (50 ml). After washingwith water, elution was carried out with 30% isopropyl alcohol, and thefractions containing a desired compound were collected and thenconcentrated under reduced pressure. The concentrate was lyophilized toobtain7-[2-(5-amino-1,3,4-thiadiazol-2-yl)-acetamido]-3-vinyl-3-cephem-4-carboxylicacid (0.31 g).

IR (Nujol): 3300, 3200, 1760, 1650, 1610, 1600, 1550, 1510 cm⁻¹.

NMR δppm (DMSO-d₆): 3.55 (2H, broad s), 3.88 (2H, s), 5.05 (1H, d, J=11Hz), 5.05 (1H, d, J=5 Hz), 5.30 (1H, d, J=17 Hz), 5.55 (1H, dd, J=5 Hz,8 Hz), 7.17 (1H, dd, J=11 Hz, 17 Hz), 9.27 (1H, d, J=8 Hz).

EXAMPLE 264

7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (0.55 g) was obtained by reacting benzhydryl7-[2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate(5 g) with trifluoroacetic acid (14.7 g) in the presence of anisole(5.57 g) according to a similar manner to that of Example 263.

IR (Nujol): 1760, 1640 cm⁻¹.

NMR δppm (DMSO-d₆): 3.55 (2H, s), 3.68 (2H, m), 5.13 (1H, d, J=5 Hz),5.28 (1H, d, J=11 Hz), 5.55 (1H, d, J=18 Hz), 5.68 (1H, dd, J=5 Hz, 8Hz), 6.95 (1H, dd, J=11 Hz, 18 Hz), 7.9 (2H, broad s), 9.05 (1H, d, J=8Hz).

EXAMPLE 265

7-[2-(5-Amino-2H-tetrazol-2-yl)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (0.7 g), mp 230°-242° C. (dec.), was obtained by reactingbenzhydryl7-[2-(5-tritylamino-2H-tetrazol-2-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate(8.3 g) with trifluoroacetic acid (24.9 g) in the presence of anisole(9.4 g) according to a similar manner to that of Example 263.

IR (Nujol): 3400-3100, 1770, 1680, 1620, 1550 cm⁻¹.

NMR δppm (DMSO-d₆): 3.7 (2H, m), 4.8-6.05 (6H, m), 7.0 (1H, dd, J=11 Hz,17 Hz), 9.57 (1H, d, J=8 Hz).

EXAMPLE 266

Conc. hydrochloric acid (0.18 g) was added to a solution of benzhydryl7-[2-(tert-butoxycarbonylmethoxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (3.0 g) in formic acid (12 ml) at 10° C. and stirred for2.5 hours at ambient temperature. The reaction mixture was poured intodiisopropyl ether (100 ml). The precipitates were collected byfiltration, washed with diisopropyl ether and dried to give7-[2-carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylicacid mono-hydrochloride (syn isomer) (1.6 g).

IR (Nujol): 1760, 1670, 1630 cm⁻¹.

NMR δppm (DMSO-d₆): 3.74 (2H, m), 4.75 (2H, s), 5.25 (1H, d, J=5.0 Hz),5.36 (1H, d, J=12.0 Hz), 5.61 (1H, d, J=18.0 Hz), 5.80 (1H, dd, J=5.0Hz, 8.0 Hz), 6.70-7.47 (1H, m), 7.06 (1H, s), 9.78 (1H, d, J=8.0 Hz).

This reaction could be carried out by using the following reagents andsolvents.

    ______________________________________                                        Reagents         Solvents  Yield (%)                                          ______________________________________                                        conc. hydrochloric acid                                                                        acetic acid                                                                             30                                                 p-toluenesulfonic acid                                                                         formic acid                                                                             90                                                 p-toluenesulfonic acid                                                                         acetic acid                                                                             50                                                 methanesulfonic acid                                                                           formic acid                                                                             89                                                 methanesulfonic acid                                                                           acetic acid                                                                             65                                                 ______________________________________                                    

EXAMPLE 267

2-Aminooxyacetic acid hemihydrochloride (1.7 g) was added to a solutionof 7-[(2-aminothiazol-4-yl)-glyoxylamido]-3-vinyl-3-cephem-4-carboxylicacid (2.0 g) and sodium acetate trihydrate (0.7 g) in water (40 ml), andthe mixture was adjusted to pH 5.2 with 10% aqueous sodium hydroxide andthen stirred for 3.5 hours at 50° C. During the stirring, the mixturewas adjusted to pH 5.0 to 5.4 with the same. The reaction mixture wasfurther adjusted to pH 2.2 with 10% hydrochloric acid under ice-cooling.The precipitates were collected by filtration, washed with water andthen dried over phosphorus pentoxide in vacuo to give7-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (1.13 g).

IR (Nujol): 3350, 1770, 1680, 1640 cm⁻¹.

The following compounds were obtained by reacting7-acylaminocephalosporanic acid derivatives having an oxo group with thecorresponding O-substituted hydroxylamine according to a similar mannerto that of Example 267.

EXAMPLE 268

7-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3400-3100, 1780, 1660, 1630, 1540 cm⁻¹.

EXAMPLE 269

Pivaloyloxymethyl7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 3400-3100, 1770, 1745, 1670, 1610, 1530 cm⁻¹.

EXAMPLE 270

Acetoxymethyl7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 3300, 1765 (broad), 1660, 1610, 1535 cm⁻¹.

EXAMPLE 271

Propionyloxymethyl7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 3350, 1770 (broad), 1650, 1620, 1530 cm⁻¹.

EXAMPLE 272

Isobutyryloxymethyl7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 3400-3100, 1780-1740, 1670, 1610, 1530 cm⁻¹.

EXAMPLE 273

1-Acetoxypropyl7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 3300, 1765, 1670, 1610 cm⁻¹.

EXAMPLE 274

L-2-Amino-2-carboxyethyl7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 3200, 1770, 1735, 1650 (broad) cm⁻¹.

EXAMPLE 275

Phthalid-3-yl7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 3300, 1775, 1670, 1610, 1530 cm⁻¹.

EXAMPLE 276

7-[2-(2-Aminothiazol-4-yl)-2-allyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3250, 1770, 1655, 1605, 1545 cm⁻¹.

EXAMPLE 277

7-[2-(2-Aminothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3250, 1760, 1680, 1620, 1530 cm⁻¹.

EXAMPLE 278

7-[2-(2-Aminothiazol-4-yl)-2-ethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer)

IR (Nujol): 3300, 1770, 1660, 1545 cm⁻¹.

EXAMPLE 279

Pivaloyloxymethyl7-[2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 3300, 1780, 1740, 1670, 1610, 1530 cm⁻¹.

EXAMPLE 280

7-[2-(2-Aminothiazol-4-yl)-2-hexyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3250, 1770, 1660, 1530 cm⁻¹.

EXAMPLE 281

7-[2-(2-Aminothiazol-4-yl)-2-(1-carboxyethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3260, 3160, 1770, 1670 cm⁻¹.

EXAMPLE 282

7-[2-(2-Aminothiazol-4-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3300, 3200, 1770, 1670, 1640 cm⁻¹.

EXAMPLE 283

7-[2-(2-Aminothiazol-4-yl)-2-(3-carboxypropoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3300, 1760, 1660 cm⁻¹.

EXAMPLE 284

7-[2-(2-Aminothiazol-4-yl)-2-ethoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3250, 1770, 1670, 1530 cm⁻¹.

EXAMPLE 285

Benzhydryl7-[2-(2-aminothiazol-4-yl)-2-(3-benzhydryloxycarbonyl-3-tert-butoxycarbonylaminopropoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 3300, 1780, 1719, 1680 cm⁻¹.

EXAMPLE 286

Benzhydryl7-[2-(2-aminothiazol-4-yl)-2-(2-benzhydryloxycarbonyl-2-tert-butoxycarbonylaminoethoxycarbonylmethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 3360, 1750 (broad) cm⁻¹.

EXAMPLE 287

7-[2-(2-Aminothiazol-4-yl)-2-(pyridin-2-ylmethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3300, 1770, 1650, 1620, 1540 cm⁻¹.

EXAMPLE 288

7-[2-(2-Aminothiazol-5-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3300, 1780, 1645, 1580, 1515 cm⁻¹.

EXAMPLE 289

7-[2-(2-Aminothiazol-4-yl)-2-cyanomethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3330, 2020, 1770, 1670, 1620 cm⁻¹.

EXAMPLE 290

7-[2-(2-Aminothiazol-4-yl)-2-(3-carboxyallyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3250, 1760, 1690, 1650 cm⁻¹.

EXAMPLE 291

7-[2-(2-Amino-5-chlorothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3400, 3180, 1770, 1685, 1650, 1610 cm⁻¹.

EXAMPLE 292

7-[2-(2-Formamidothiazol-4-yl)-2-(0,0-diethylphosphonomethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3160, 1775 (broad), 1680 (broad) cm⁻¹.

EXAMPLE 293

7-[2-(2-Aminothiazol-4-yl)-2-(2-cyclopenten-1-yloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3270, 1765, 1650 cm⁻¹.

EXAMPLE 294

7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3350, 3250, 1770, 1670, 1620, 1530 cm⁻¹.

EXAMPLE 295

Pivaloyloxymethyl7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 3400-3100, 1770, 1760, 1680, 1620, 1530 cm⁻¹.

EXAMPLE 296

7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3380, 3280, 1760, 1720, 1670 cm⁻¹.

EXAMPLE 297

7-[2-(5-Amino-1,2,4-oxadiazol-3-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3250, 1770, 1660, 1550 cm⁻¹.

EXAMPLE 298

7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3350, 3250, 1780 (broad), 1667 (broad) cm⁻¹.

EXAMPLE 299

7-[2-(6-Aminopyridin-2-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3300, 1763 (broad), 1660 (broad) cm⁻¹.

EXAMPLE 300

Benzhydryl7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 3250, 1780, 1710, 1700, 1660, 1540 cm⁻¹.

EXAMPLE 301

Benzhydryl7-[2-(2-formamidothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 3250, 1780, 1720, 1680, 1540 cm⁻¹.

EXAMPLE 302

Benzhydryl7-[2-(2-aminothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 3440, 3260, 3100, 1780, 1720, 1660, 1530 cm⁻¹.

EXAMPLE 303

2-(1-tert-Butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer) (2.2 g) was added to the stirred suspension ofphosphorus pentachloride (1.6 g) in methylene chloride (22 ml) at -15°C., and the mixture was stirred for 30 minutes at -5° to -15° C. Drydiisopropyl ether was added to the reaction mixture at -10° C., and theprecipitates were collected by filtration, washed with dry diisopropylether. On the other hand, trimethylsilylacetamide (5.4 g) was added tothe stirred suspension of benzhydryl7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (2.5 g) inmethylene chloride (25 ml). To the solution obtained were added theabove precipitates at -10° C. and stirred at -5° to -10° C. for 40minutes. Water was added to the resultant solution and the separatedorganic layer was washed with a saturated aqueous sodium bicarbonate anda saturated aqueous sodium chloride, dried over magnesium sulfate, andthen evaporated to give benzhydryl7-[2-(1-tert-butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (2.51 g).

IR (Nujol): 1770, 1720, 1680, 1610 cm⁻¹.

EXAMPLE 304

7-[2-(4-tert-Butoxycarbonylaminothiazol-2-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (0.95 g) was obtained by reacting7-amino-3-vinyl-3-cephem-4-carboxylic acid (0.7 g) with2-(4-tert-butoxycarbonylaminothiazol-2-yl)-2-methoxyiminoacetic acid(syn isomer) (0.9 g) according to a similar manner to that of Example 7.

IR (Nujol): 3250, 1785, 1720, 1690, 1600, 1535 cm⁻¹.

NMR δppm (DMSO-d6): 1.45 (9H, s), 3.72 (2H, q, J=17 Hz), 3.95 (3H, s),5.18 (1H, d, J=5 Hz), 5.28 (1H, d, J=11 Hz), 5.52 (1H, d, J=17 Hz), 5.82(1H, dd, J=5 Hz, 8 Hz), 5.90 (1H, dd, J=11 Hz, 17 Hz), 7.28 (1H, s),9.71 (1H, d, J=8 Hz), 10.27 (1H, s).

EXAMPLE 305

Trifluoroacetic acid (9.6 ml) was added to a solution of benzhydryl7-[2-(1-tert-butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate(syn isomer) (2.4 g) in methylene chloride (5 ml) and anisole (2.4 ml)under ice-cooling, and the mixture was stirred for 1 hour at roomtemperature. The resultant solution was added dropwise to diisopropylether (100 ml) and the precipitates were collected by filtration. Theprecipitates were added to a mixture of water and ethyl acetate and thenadjusted to pH 7.5 with 10% aqueous sodium hydroxide. The separatedaqueous layer was saturated with sodium chloride and adjusted to pH 1.5with 10% hydrochloric acid, followed by extraction with a mixed solventof ethyl acetate and tetrahydrofuran (1:1 by volume). The extract waswashed with a saturated aqueous sodium chloride and dried over magnesiumsulfate. Removal of the solvent gave7-[2-(1-carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (0.55 g).

    ______________________________________                                        IR (Nujol):                                                                   3330, 3200, 1770, 1670, 1610 cm.sup.-1                                        NMR δ ppm (DMSO-d6):                                                    1.37 (3 H, m), 3.70 (2 H, m),                                                 4.80 (1 H, m), 5.07-6.07 (4 H, m),                                            6.96 (1 H, d,d J = 12.0 Hz, 18.0 Hz),                                         8.17 (2 H, broad s),                                                          9.47 (d, J = 8.0 Hz)                                                           (1 H)                                                                        9.55 (d, J = 8.0 Hz)                                                          ______________________________________                                    

EXAMPLE 306

To ethanol (2 l) was added7-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (70 g), and the mixture was stirred at 40° C. for 30minutes. The insoluble substance was collected by filtration and washedwith ethanol. The washings and the filtrate were combined, and theretowas added water (4.2 l) at 40° C., followed by stirring at ambienttemperature for an hour. The precipitates were collected by filtrationto obtain crystalline trihydrate of7-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid (syn isomer) (61.6 g).

    ______________________________________                                        X-ray spectrum:                                                               2θ°                                                                         I/I.sub.0 (relative intensity)                                     ______________________________________                                        29.9°                                                                             0.40                                                               28.7       0.17                                                               28.4       0.23                                                               28.0       0.15                                                               27.3       0.69                                                               26.4       0.53                                                               26.1       0.43                                                               24.7       0.42                                                               23.7       0.53                                                               23.4       0.70                                                               23.1       0.50                                                               22.7       0.69                                                               22.2       0.82                                                               21.4       0.40                                                               21.0       0.50                                                               20.5       0.54                                                               20.0       0.30                                                               19.5       1.00                                                               17.5       0.10                                                               15.4       0.48                                                               15.0       0.93                                                               8.9        0.93                                                               7.5        0.15                                                               5.8        0.34                                                               ______________________________________                                    

What we claim is:
 1. A compound of the formula: ##STR28## in which R¹ is aminothiazolyl which may have halogen, aminothiadiazolyl, aminooxadiazolyl, aminopyridyl, aminopyrimidinyl, lower alkanamidothiazolyl which may have halogen, lower alkoxycarbonylaminothiazolyl, di(lower)alkylaminomethyleneaminothiadiazolyl, di(lower)alkylaminomethyleneaminooxadiazolyl, or lower alkanamidopyridyl,R² is carboxy or a pharmaceutically acceptable esterified carboxy group, and R⁴ is hydrogen, cyclo(lower)alkenyl, lower alkynyl, lower alkenyl, lower alkenyl substituted by carboxy or a pharmaceutically acceptable esterified carboxy group, lower alkyl, or alkyl, or lower alkyl substituted by one or more substituents selected from amino, lower alkoxycarbonylamino, cyano, phosphono, O,O-di(lower)alkylphosphono and pyridyl, and a pharmaceutically acceptable salt thereof.
 2. A compound of claim 1, which is syn isomer.
 3. A compound of claim 2, in whichR¹ is 2-aminothiazol-4-yl, 2-amino-5-halothiazol-4-yl, 2-aminothiazol-5-yl, 5-amino-1,2,4-thiadiazol-3-yl, 5-amino-1,2,4-oxadiazol-3-yl, 6-aminopyridin-2-yl, or 4-aminopyrimidin-2-yl.
 4. A compound of claim 3, in whichR⁴ is cyclo(lower)alkenyl, lower alkynyl, lower alkenyl, carboxy(lower)alkenyl, esterified carboxy(lower)alkenyl, lower alkyl, carboxy(lower)alkyl, esterified carboxy(lower)alkyl, amino- and carboxy-substituted-lower alkyl, acylamino- and esterified carboxy-substituted-lower alkyl, cyano(lower)alkyl, phosphono(lower)alkyl, esterified phosphono(lower)alkyl, or pyridyl(lower)alkyl.
 5. A compound of claim 4, in which R² is carboxy.
 6. A compound of claim 5, in which R¹ is 2-aminothiazol-4-yl and R⁴ is lower alkyl.
 7. A compound of claim 6, which is7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid or its sodium salt.
 8. A compound of claim 4, in which R² is mono- or di- or triphenyl(lower)alkoxycarbonyl, lower alkanoyloxy(lower)alkoxycarbonyl, amino- and carboxy-substituted-lower alkoxycarbonyl, or lower alkoxycarbonylamino- and mono- or di- or triphenyl(lower)alkoxycarbonyl-substituted-lower alkoxycarbonyl.
 9. A compound of claim 8, in whichR¹ is 2-aminothiazol-4-yl and R⁴ is lower alkyl.
 10. A compound of claim 9, which is pivaloyloxymethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate.
 11. A compound of claim 2, which is7-[2-(2-aminothiazol-4-yl)-2-{(1-methyl-3-pyridinio)methoxyimino}acetamido]-3-vinyl-3-cephem-4-carboxylate or its hydrochloride, 7-[2-(2-aminothiazol-4-yl)-2-{(1-methyl-2-pyridinio)methoxyimino}acetamido]-3-vinyl-3-cephem-4-carboxylate or its hydrochloride, 1-methyl-3-[1-(2-aminothiazol-4-yl)-1-{N-(4-benzhydryloxycarbonyl-3-vinyl-3-cephem-7-yl)-carbamoyl}methyleneaminooxymethyl]pyridinium methylsulfate or its hydrochloride, or 1-methyl-2-[1-(2-aminothiazol-4-yl)-1-{N-(4-benzhydryloxycarbonyl-3-vinyl-3-cephem-7-yl)-carbamoyl}methyleneaminooxymethyl]pyridinium methylsulfate or its hydrochloride.
 12. An antimicrobial pharmaceutical composition comprising, as active ingredients, an effective amount of the compound claimed in claim 1, in admixture with pharmaceutically acceptable carriers.
 13. A method for treating an infectious disease caused by pathogenic microorganisms, which comprises administering an effective amount of a compound claimed in claim 1 to infected human beings or animals. 